This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported in patients with ovarian cancer [PMID 26315354]
ClinVar Genomic variation as it relates to human health
NM_024675.4(PALB2):c.3296C>G (p.Thr1099Arg)
Germline
Classification
Help
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
(20)
Help
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Conflicting classifications of pathogenicity
Uncertain significance(17); Likely benign(2)
Uncertain significance(17); Likely benign(2)
20
criteria provided, conflicting classifications
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_024675.4(PALB2):c.3296C>G (p.Thr1099Arg)
Variation ID: 142504 Accession: VCV000142504.49
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 16p12.2 16: 23607918 (GRCh38) [ NCBI UCSC ] 16: 23619239 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Oct 9, 2016 Oct 13, 2024 Oct 4, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_024675.4:c.3296C>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_078951.2:p.Thr1099Arg missense NC_000016.10:g.23607918G>C NC_000016.9:g.23619239G>C NG_007406.1:g.38440C>G LRG_308:g.38440C>G LRG_308t1:c.3296C>G LRG_308p1:p.Thr1099Arg - Protein change
- T1099R
- Other names
- -
- Canonical SPDI
- NC_000016.10:23607917:G:C
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
-
0.00020 (A)
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
Trans-Omics for Precision Medicine (TOPMed) 0.00002
The Genome Aggregation Database (gnomAD) 0.00003
- Links
Genes
| Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
|---|---|---|---|---|---|---|
| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
|||
| PALB2 | - | - |
GRCh38 GRCh37 |
5923 | 5965 | |
Conditions - Germline
| Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
|---|---|---|---|---|
| Uncertain significance (6) |
criteria provided, multiple submitters, no conflicts
|
Jul 24, 2023 | RCV000131652.19 | |
| Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
|
Dec 11, 2023 | RCV000235868.13 | |
| Conflicting interpretations of pathogenicity (5) |
criteria provided, conflicting classifications
|
Feb 21, 2024 | RCV000410212.20 | |
| Uncertain significance (4) |
criteria provided, multiple submitters, no conflicts
|
Oct 4, 2024 | RCV000657014.15 | |
| Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
|
Mar 10, 2020 | RCV001294230.5 | |
| Uncertain significance (1) |
criteria provided, single submitter
|
Mar 10, 2022 | RCV002478400.1 |
Submissions - Germline
| Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
|
|---|---|---|---|---|---|
|
Uncertain significance
(Jun 14, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: no
Allele origin:
germline
|
Genetic Services Laboratory, University of Chicago
Accession: SCV000596218.1
First in ClinVar: Oct 09, 2016 Last updated: Oct 09, 2016 |
|
|
|
Uncertain significance
(Nov 29, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV000807106.1
First in ClinVar: Jul 09, 2018 Last updated: Jul 09, 2018 |
|
|
|
Uncertain significance
(Mar 21, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Fanconi anemia complementation group N
Affected status: yes
Allele origin:
unknown
|
Baylor Genetics
Study: CSER-TexasKidsCanSeq
Accession: SCV001483087.1 First in ClinVar: Mar 07, 2021 Last updated: Mar 07, 2021 |
Comment:
This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported in patients with ovarian … (more)
This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported in patients with ovarian cancer [PMID 26315354] (less)
|
|
|
Uncertain significance
(Jan 12, 2022)
|
criteria provided, single submitter
Method: curation
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Sema4, Sema4
Accession: SCV002531162.1
First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022
Comment:
The PALB2 c.3296C>G (p.T1099R) variant has been reported in at least 3 individuals with breast and/or ovarian cancer and 1 individual with colon and bladder … (more)
The PALB2 c.3296C>G (p.T1099R) variant has been reported in at least 3 individuals with breast and/or ovarian cancer and 1 individual with colon and bladder cancer (PMID: 25186627, 26315354, 26976419, 30883245, 31159747). The variant was detected with similar frequency between cases and controls from a breast cancer case-control study (PMID: 33471991). In silico tools suggest the impact of the variant on protein function is inconclusive. However, a homology-directed repair study demonstrated the normal function of the protein (PMID: 31636395). It was observed in 17/282868 chromosomes across the large and broad cohorts of the Genome Aggregation Database (http://gnomad.broadinstitute.org, PMID: 32461654). The variant has been reported in ClinVar (Variation ID 142504). The evidence is insufficient to meet ACMG/AMP criteria for classifying the variant as benign or pathogenic. Thus, the clinical significance of this variant is currently uncertain. (less)
|
|
|
|
Uncertain significance
(Jul 02, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
unknown
|
Mendelics
Accession: SCV000838996.2
First in ClinVar: Oct 10, 2018 Last updated: Dec 11, 2022 |
|
|
|
Uncertain significance
(Mar 22, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
Familial cancer of breast
Affected status: unknown
Allele origin:
unknown
|
Counsyl
Accession: SCV000488413.2
First in ClinVar: Jan 06, 2017 Last updated: Dec 24, 2022 |
|
|
|
Uncertain significance
(Dec 11, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000919934.4
First in ClinVar: Jun 02, 2019 Last updated: Feb 04, 2024 |
Comment:
Variant summary: PALB2 c.3296C>G (p.Thr1099Arg) results in a non-conservative amino acid change located in the Partner and localiser of BRCA2, WD40 domain (IPR031920) of the … (more)
Variant summary: PALB2 c.3296C>G (p.Thr1099Arg) results in a non-conservative amino acid change located in the Partner and localiser of BRCA2, WD40 domain (IPR031920) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 6.5e-05 in 263146 control chromosomes, predominantly at a frequency of 0.00016 within the South Asian subpopulation in the gnomAD database (5 occurrences). This frequency is equal to the estimated maximal expected allele frequency of a pathogenic PALB2 variant causing Hereditary Breast and Ovarian Cancer (0.00016), suggesting this may be a benign polymorphism. c.3296C>G has been reported in the literature as a VUS in individuals affected with Breast and/or Ovarian Cancer, colon and bladder cancer (example, Ramus_2015, Tung_2015, Tung_2016, Abe_2019, Zhunussova_2019). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. At-least one co-occurrence with another pathogenic variant has been observed at our laboratory (ATM c.901+1G>A), providing supporting evidence for a benign role. At least one functional study reports the result of HDR assay showed no damaging effect of this variant (Wiltshire_2019). The following publications have been ascertained in the context of this evaluation (PMID: 30883245, 35610400, 31422574, 26315354, 25186627, 26976419, 31636395, 31428572). Multiple submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified as VUS (n=16) and likely benign (n=1). Based on the evidence outlined above, the variant was classified as VUS-possibly benign. (less)
|
|
|
Uncertain significance
(Jan 24, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Color Diagnostics, LLC DBA Color Health
Accession: SCV000537595.6
First in ClinVar: Sep 24, 2016 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces threonine with arginine at codon 1099 of the PALB2 protein. Computational prediction suggests that this variant may not impact protein structure … (more)
This missense variant replaces threonine with arginine at codon 1099 of the PALB2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). A functional study has shown that this variant does not affect the homology-directed DNA repair function of PALB2 protein (PMID: 31636395). This variant has been reported in individuals affected with breast cancer (PMID: 25186627, 26976419, 28779002), bladder and colorectal cancer (PMID: 30883245), and ovarian cancer (PMID: 26315354), and this variant has been detected in a breast cancer case-control meta-analysis in 6/60466 cases and 4/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID PALB2_010286). This variant has been reported in 1 individual age 70 years or older without cancer in the FLOSSIES database (https://whi.color.com/variant/16-23619239-G-C), and it also has been identified in 17/282868 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. (less)
|
|
|
Uncertain significance
(Feb 21, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Familial cancer of breast
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV004201989.2
First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024 |
|
|
|
Uncertain significance
(-)
|
criteria provided, single submitter
Method: not provided
|
not provided
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
|
Breakthrough Genomics, Breakthrough Genomics
Accession: SCV005194279.1
First in ClinVar: Aug 18, 2024 Last updated: Aug 18, 2024 |
|
|
|
Uncertain significance
(Oct 04, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000292841.15
First in ClinVar: Jul 24, 2016 Last updated: Oct 13, 2024 |
Comment:
Published functional studies demonstrate no damaging effect: homology directed DNA repair activity similar to wild type (PMID: 31636395); In silico analysis supports that this missense … (more)
Published functional studies demonstrate no damaging effect: homology directed DNA repair activity similar to wild type (PMID: 31636395); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with breast, ovarian, pancreatic, or colorectal cancer, but also in unaffected controls (PMID: 26315354, 28779002, 25186627, 31428572, 33471991, 30883245, 36627197, 35610400); This variant is associated with the following publications: (PMID: 25186627, 26315354, 26976419, 28779002, 31159747, 31422574, 30883245, 33471991, 31428572, 31636395, 24485656, 19609323, 20871615, 36627197, 35610400, 38476606, 35402282) (less)
|
|
|
Uncertain significance
(Aug 01, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
GeneKor MSA
Accession: SCV000822115.1
First in ClinVar: Oct 10, 2018 Last updated: Oct 10, 2018 |
|
|
|
Uncertain significance
(Mar 10, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Familial cancer of breast
Fanconi anemia complementation group N Pancreatic cancer, susceptibility to, 3
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV002788083.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
|
|
|
Uncertain significance
(Nov 15, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.
Accession: SCV002819220.1
First in ClinVar: Jan 15, 2023 Last updated: Jan 15, 2023 |
|
|
|
Likely benign
(Mar 31, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Familial cancer of breast
Affected status: unknown
Allele origin:
unknown
|
Myriad Genetics, Inc.
Accession: SCV004019628.1
First in ClinVar: Jul 29, 2023 Last updated: Jul 29, 2023 |
Comment:
This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic … (more)
This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752]. (less)
|
|
|
Uncertain significance
(Aug 12, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
unknown
|
Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV001134551.4
First in ClinVar: Jan 05, 2020 Last updated: Jan 06, 2024 |
Comment:
In the published literature, this variant has been reported in individuals affected with breast cancer (PMIDs: 35402282 (2022), 26976419 (2016), 25186627 (2015)), ovarian cancer (PMID: … (more)
In the published literature, this variant has been reported in individuals affected with breast cancer (PMIDs: 35402282 (2022), 26976419 (2016), 25186627 (2015)), ovarian cancer (PMID: 26315354 (2015)), and colorectal cancer (PMIDs: 31428572 (2019), 30883245 (2019)). The variant was also reported in an individual without a cancer diagnosis (PMID: 31422574 (2019)). The variant was detected in both cases and controls from a large breast cancer study (PMID: 33471991 (2021), https://databases.lovd.nl/shared/genes/PALB2). An in vivo functional study shows that the variant results in no damaging effect on protein function (PMID: 31636395 (2020)). The frequency of this variant in the general population, 0.00029 (3/10370 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant. (less)
|
|
|
Uncertain significance
(Mar 10, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Fanconi anemia complementation group N
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV003812299.2
First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024 |
|
|
|
Likely benign
(Jan 10, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Familial cancer of breast
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000550779.11
First in ClinVar: Jan 06, 2017 Last updated: Feb 20, 2024 |
|
|
|
Uncertain significance
(Jul 24, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000186679.9
First in ClinVar: Aug 06, 2014 Last updated: May 01, 2024 |
Comment:
The p.T1099R variant (also known as c.3296C>G), located in coding exon 12 of the PALB2 gene, results from a C to G substitution at nucleotide … (more)
The p.T1099R variant (also known as c.3296C>G), located in coding exon 12 of the PALB2 gene, results from a C to G substitution at nucleotide position 3296. The threonine at codon 1099 is replaced by arginine, an amino acid with similar properties. This alteration has previously been reported in individuals at risk for hereditary breast, ovarian, and pancreatic cancers (Tung N et al. Cancer. 2015 Jan;121(1):25-33; Ramus SJ et al. J. Natl. Cancer Inst. 2015 Aug;27;107(11); Decker B et al. J Med Genet. 2017 11;54:732-741; Abe T et al. J. Clin. Oncol. 2019 05;37(13):1070-1080; Tsaousis GN et al. BMC Cancer. 2019 Jun;19:535). This variant was also reported in 6/60,466 breast cancer cases and in 4/53,461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). This alteration was found to be functional in a homology-directed DNA repair (HDR) assay (Wiltshire T et al. Genet. Med. 2020 Mar;22(3):622-632). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)
|
|
|
Uncertain significance
(May 13, 2019)
|
no assertion criteria provided
Method: curation
|
Familial cancer of breast
Affected status: yes
Allele origin:
germline
|
Leiden Open Variation Database
Accession: SCV001193386.1
First in ClinVar: Apr 06, 2020 Last updated: Apr 06, 2020 |
Comment:
Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitter to LOVD: Marc Tischkowitz.
|
|
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Comment:
Comment:
Variant summary: PALB2 c.3296C>G (p.Thr1099Arg) results in a non-conservative amino acid change located in the Partner and localiser of BRCA2, WD40 domain (IPR031920) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 6.5e-05 in 263146 control chromosomes, predominantly at a frequency of 0.00016 within the South Asian subpopulation in the gnomAD database (5 occurrences). This frequency is equal to the estimated maximal expected allele frequency of a pathogenic PALB2 variant causing Hereditary Breast and Ovarian Cancer (0.00016), suggesting this may be a benign polymorphism. c.3296C>G has been reported in the literature as a VUS in individuals affected with Breast and/or Ovarian Cancer, colon and bladder cancer (example, Ramus_2015, Tung_2015, Tung_2016, Abe_2019, Zhunussova_2019). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. At-least one co-occurrence with another pathogenic variant has been observed at our laboratory (ATM c.901+1G>A), providing supporting evidence for a benign role. At least one functional study reports the result of HDR assay showed no damaging effect of this variant (Wiltshire_2019). The following publications have been ascertained in the context of this evaluation (PMID: 30883245, 35610400, 31422574, 26315354, 25186627, 26976419, 31636395, 31428572). Multiple submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified as VUS (n=16) and likely benign (n=1). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Comment:
This missense variant replaces threonine with arginine at codon 1099 of the PALB2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). A functional study has shown that this variant does not affect the homology-directed DNA repair function of PALB2 protein (PMID: 31636395). This variant has been reported in individuals affected with breast cancer (PMID: 25186627, 26976419, 28779002), bladder and colorectal cancer (PMID: 30883245), and ovarian cancer (PMID: 26315354), and this variant has been detected in a breast cancer case-control meta-analysis in 6/60466 cases and 4/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID PALB2_010286). This variant has been reported in 1 individual age 70 years or older without cancer in the FLOSSIES database (https://whi.color.com/variant/16-23619239-G-C), and it also has been identified in 17/282868 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Comment:
Published functional studies demonstrate no damaging effect: homology directed DNA repair activity similar to wild type (PMID: 31636395); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with breast, ovarian, pancreatic, or colorectal cancer, but also in unaffected controls (PMID: 26315354, 28779002, 25186627, 31428572, 33471991, 30883245, 36627197, 35610400); This variant is associated with the following publications: (PMID: 25186627, 26315354, 26976419, 28779002, 31159747, 31422574, 30883245, 33471991, 31428572, 31636395, 24485656, 19609323, 20871615, 36627197, 35610400, 38476606, 35402282)
Comment:
This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752].
Comment:
In the published literature, this variant has been reported in individuals affected with breast cancer (PMIDs: 35402282 (2022), 26976419 (2016), 25186627 (2015)), ovarian cancer (PMID: 26315354 (2015)), and colorectal cancer (PMIDs: 31428572 (2019), 30883245 (2019)). The variant was also reported in an individual without a cancer diagnosis (PMID: 31422574 (2019)). The variant was detected in both cases and controls from a large breast cancer study (PMID: 33471991 (2021), https://databases.lovd.nl/shared/genes/PALB2). An in vivo functional study shows that the variant results in no damaging effect on protein function (PMID: 31636395 (2020)). The frequency of this variant in the general population, 0.00029 (3/10370 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
Comment:
The p.T1099R variant (also known as c.3296C>G), located in coding exon 12 of the PALB2 gene, results from a C to G substitution at nucleotide position 3296. The threonine at codon 1099 is replaced by arginine, an amino acid with similar properties. This alteration has previously been reported in individuals at risk for hereditary breast, ovarian, and pancreatic cancers (Tung N et al. Cancer. 2015 Jan;121(1):25-33; Ramus SJ et al. J. Natl. Cancer Inst. 2015 Aug;27;107(11); Decker B et al. J Med Genet. 2017 11;54:732-741; Abe T et al. J. Clin. Oncol. 2019 05;37(13):1070-1080; Tsaousis GN et al. BMC Cancer. 2019 Jun;19:535). This variant was also reported in 6/60,466 breast cancer cases and in 4/53,461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). This alteration was found to be functional in a homology-directed DNA repair (HDR) assay (Wiltshire T et al. Genet. Med. 2020 Mar;22(3):622-632). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Comment:
Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitter to LOVD: Marc Tischkowitz.
Germline Functional Evidence
| There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Comment:
This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported in patients with ovarian cancer [PMID 26315354]
Comment:
Variant summary: PALB2 c.3296C>G (p.Thr1099Arg) results in a non-conservative amino acid change located in the Partner and localiser of BRCA2, WD40 domain (IPR031920) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 6.5e-05 in 263146 control chromosomes, predominantly at a frequency of 0.00016 within the South Asian subpopulation in the gnomAD database (5 occurrences). This frequency is equal to the estimated maximal expected allele frequency of a pathogenic PALB2 variant causing Hereditary Breast and Ovarian Cancer (0.00016), suggesting this may be a benign polymorphism. c.3296C>G has been reported in the literature as a VUS in individuals affected with Breast and/or Ovarian Cancer, colon and bladder cancer (example, Ramus_2015, Tung_2015, Tung_2016, Abe_2019, Zhunussova_2019). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. At-least one co-occurrence with another pathogenic variant has been observed at our laboratory (ATM c.901+1G>A), providing supporting evidence for a benign role. At least one functional study reports the result of HDR assay showed no damaging effect of this variant (Wiltshire_2019). The following publications have been ascertained in the context of this evaluation (PMID: 30883245, 35610400, 31422574, 26315354, 25186627, 26976419, 31636395, 31428572). Multiple submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified as VUS (n=16) and likely benign (n=1). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Comment:
This missense variant replaces threonine with arginine at codon 1099 of the PALB2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). A functional study has shown that this variant does not affect the homology-directed DNA repair function of PALB2 protein (PMID: 31636395). This variant has been reported in individuals affected with breast cancer (PMID: 25186627, 26976419, 28779002), bladder and colorectal cancer (PMID: 30883245), and ovarian cancer (PMID: 26315354), and this variant has been detected in a breast cancer case-control meta-analysis in 6/60466 cases and 4/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID PALB2_010286). This variant has been reported in 1 individual age 70 years or older without cancer in the FLOSSIES database (https://whi.color.com/variant/16-23619239-G-C), and it also has been identified in 17/282868 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Comment:
Published functional studies demonstrate no damaging effect: homology directed DNA repair activity similar to wild type (PMID: 31636395); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with breast, ovarian, pancreatic, or colorectal cancer, but also in unaffected controls (PMID: 26315354, 28779002, 25186627, 31428572, 33471991, 30883245, 36627197, 35610400); This variant is associated with the following publications: (PMID: 25186627, 26315354, 26976419, 28779002, 31159747, 31422574, 30883245, 33471991, 31428572, 31636395, 24485656, 19609323, 20871615, 36627197, 35610400, 38476606, 35402282)
Comment:
This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752].
Comment:
In the published literature, this variant has been reported in individuals affected with breast cancer (PMIDs: 35402282 (2022), 26976419 (2016), 25186627 (2015)), ovarian cancer (PMID: 26315354 (2015)), and colorectal cancer (PMIDs: 31428572 (2019), 30883245 (2019)). The variant was also reported in an individual without a cancer diagnosis (PMID: 31422574 (2019)). The variant was detected in both cases and controls from a large breast cancer study (PMID: 33471991 (2021), https://databases.lovd.nl/shared/genes/PALB2). An in vivo functional study shows that the variant results in no damaging effect on protein function (PMID: 31636395 (2020)). The frequency of this variant in the general population, 0.00029 (3/10370 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
Comment:
The p.T1099R variant (also known as c.3296C>G), located in coding exon 12 of the PALB2 gene, results from a C to G substitution at nucleotide position 3296. The threonine at codon 1099 is replaced by arginine, an amino acid with similar properties. This alteration has previously been reported in individuals at risk for hereditary breast, ovarian, and pancreatic cancers (Tung N et al. Cancer. 2015 Jan;121(1):25-33; Ramus SJ et al. J. Natl. Cancer Inst. 2015 Aug;27;107(11); Decker B et al. J Med Genet. 2017 11;54:732-741; Abe T et al. J. Clin. Oncol. 2019 05;37(13):1070-1080; Tsaousis GN et al. BMC Cancer. 2019 Jun;19:535). This variant was also reported in 6/60,466 breast cancer cases and in 4/53,461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). This alteration was found to be functional in a homology-directed DNA repair (HDR) assay (Wiltshire T et al. Genet. Med. 2020 Mar;22(3):622-632). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Comment:
Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitter to LOVD: Marc Tischkowitz.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| PALB2 germline mutations in a multi-gene panel testing cohort of 1905 breast-ovarian cancer patients in Argentina. | Gonzalez A | Breast cancer research and treatment | 2022 | PMID: 35610400 |
| Rates of Variants of Uncertain Significance Among Patients With Breast Cancer Undergoing Genetic Testing: Regional Perspectives. | Abdel-Razeq H | Frontiers in oncology | 2022 | PMID: 35402282 |
| Breast Cancer Risk Genes - Association Analysis in More than 113,000 Women. | Breast Cancer Association Consortium | The New England journal of medicine | 2021 | PMID: 33471991 |
| Functional characterization of 84 PALB2 variants of uncertain significance. | Wiltshire T | Genetics in medicine : official journal of the American College of Medical Genetics | 2020 | PMID: 31636395 |
| Mutation Spectrum of Cancer-Associated Genes in Patients With Early Onset of Colorectal Cancer. | Zhunussova G | Frontiers in oncology | 2019 | PMID: 31428572 |
| Prevalence of genetic susceptibility for breast and ovarian cancer in a non-cancer related study population: secondary germline findings from a Swiss single centre cohort. | Kraemer D | Swiss medical weekly | 2019 | PMID: 31422574 |
| Analysis of hereditary cancer syndromes by using a panel of genes: novel and multiple pathogenic mutations. | Tsaousis GN | BMC cancer | 2019 | PMID: 31159747 |
| Deleterious Germline Mutations Are a Risk Factor for Neoplastic Progression Among High-Risk Individuals Undergoing Pancreatic Surveillance. | Abe T | Journal of clinical oncology : official journal of the American Society of Clinical Oncology | 2019 | PMID: 30883245 |
| Rare, protein-truncating variants in ATM, CHEK2 and PALB2, but not XRCC2, are associated with increased breast cancer risks. | Decker B | Journal of medical genetics | 2017 | PMID: 28779002 |
| Frequency of Germline Mutations in 25 Cancer Susceptibility Genes in a Sequential Series of Patients With Breast Cancer. | Tung N | Journal of clinical oncology : official journal of the American Society of Clinical Oncology | 2016 | PMID: 26976419 |
| Germline Mutations in the BRIP1, BARD1, PALB2, and NBN Genes in Women With Ovarian Cancer. | Ramus SJ | Journal of the National Cancer Institute | 2015 | PMID: 26315354 |
| Frequency of mutations in individuals with breast cancer referred for BRCA1 and BRCA2 testing using next-generation sequencing with a 25-gene panel. | Tung N | Cancer | 2015 | PMID: 25186627 |
| Development and validation of a new algorithm for the reclassification of genetic variants identified in the BRCA1 and BRCA2 genes. | Pruss D | Breast cancer research and treatment | 2014 | PMID: 25085752 |
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Text-mined citations for rs142132127 ...
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Record last updated Oct 20, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.