This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1035 of the PALB2 protein (p.Ile1035Val). This variant is present in population databases (no rsID available, gnomAD 0.006%). This missense change has been observed in individual(s) with endometrial cancer, chordoma, and hereditary breast and ovarian cancer (PMID: 27443514, 34284872, 35762214). ClinVar contains an entry for this variant (Variation ID: 216750). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt PALB2 protein function. Experimental studies have shown that this missense change affects PALB2 function (PMID: 35762214). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
ClinVar Genomic variation as it relates to human health
NM_024675.4(PALB2):c.3103A>G (p.Ile1035Val)
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.
(9)
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(7); Likely benign(1)
Uncertain significance(7); Likely benign(1)
9
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.3103A>G (p.Ile1035Val)
Variation ID: 216750 Accession: VCV000216750.21
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 16p12.2 16: 23621372 (GRCh38) [ NCBI UCSC ] 16: 23632693 (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 May 26, 2018 May 1, 2024 Oct 30, 2023 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_024675.4:c.3103A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_078951.2:p.Ile1035Val missense NC_000016.10:g.23621372T>C NC_000016.9:g.23632693T>C NG_007406.1:g.24986A>G LRG_308:g.24986A>G LRG_308t1:c.3103A>G LRG_308p1:p.Ile1035Val - Protein change
- I1035V
- Other names
- -
- Canonical SPDI
- NC_000016.10:23621371:T: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.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
The Genome Aggregation Database (gnomAD), exomes 0.00001
- 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 |
5921 | 5963 | |
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 (4) |
criteria provided, multiple submitters, no conflicts
|
Oct 30, 2023 | RCV000196785.14 | |
| Conflicting interpretations of pathogenicity (3) |
criteria provided, conflicting classifications
|
Sep 28, 2022 | RCV000220160.13 | |
| Uncertain significance (1) |
criteria provided, single submitter
|
Dec 20, 2021 | RCV001797063.3 | |
| Uncertain significance (1) |
no assertion criteria provided
|
Mar 22, 2021 | RCV002266931.1 |
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
(Oct 15, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Familial cancer of breast
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000255096.10
First in ClinVar: Oct 11, 2015 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1035 of the PALB2 protein (p.Ile1035Val). … (more)
This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1035 of the PALB2 protein (p.Ile1035Val). This variant is present in population databases (no rsID available, gnomAD 0.006%). This missense change has been observed in individual(s) with endometrial cancer, chordoma, and hereditary breast and ovarian cancer (PMID: 27443514, 34284872, 35762214). ClinVar contains an entry for this variant (Variation ID: 216750). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt PALB2 protein function. Experimental studies have shown that this missense change affects PALB2 function (PMID: 35762214). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
|
|
|
Uncertain significance
(Sep 28, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000276342.8
First in ClinVar: May 29, 2016 Last updated: May 01, 2024 |
Comment:
The p.I1035V variant (also known as c.3103A>G), located in coding exon 10 of the PALB2 gene, results from an A to G substitution at nucleotide … (more)
The p.I1035V variant (also known as c.3103A>G), located in coding exon 10 of the PALB2 gene, results from an A to G substitution at nucleotide position 3103. The isoleucine at codon 1035 is replaced by valine, an amino acid with highly similar properties. This alteration has been previously detected in a cohort of 381 unselected endometrial cancer patients who underwent multi-gene panel testing (Ring KL et al. Mod. Pathol., 2016 11;29:1381-1389). The alteration was also identified in 1/6385 invasive epithelial ovarian cancer cases and 1/6114 controls of European ancestry (Song H et al. J Med Genet, 2021 05;58:305-313) and in 1/60,466 breast cancer cases and 1/53,461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)
|
|
|
Uncertain significance
(Dec 19, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Familial cancer of breast
Affected status: unknown
Allele origin:
unknown
|
Counsyl
Accession: SCV000785829.2
First in ClinVar: May 26, 2018 Last updated: May 26, 2018 |
|
|
|
Likely benign
(Apr 24, 2015)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Color Diagnostics, LLC DBA Color Health
Accession: SCV000902929.1
First in ClinVar: May 20, 2019 Last updated: May 20, 2019 |
|
|
|
Uncertain significance
(Jan 12, 2022)
|
criteria provided, single submitter
Method: curation
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Sema4, Sema4
Accession: SCV002530750.1
First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022
Comment:
The PALB2 c.3103A>G (p.I1035V) variant has been reported in individuals with endometrial carcinoma, ovarian cancer as wells as in controls (PMID: 27443514, 32546565). Additionally, it … (more)
The PALB2 c.3103A>G (p.I1035V) variant has been reported in individuals with endometrial carcinoma, ovarian cancer as wells as in controls (PMID: 27443514, 32546565). Additionally, it was observed in a large case-control study in 1/60466 breast cancer cases and 1/53461 controls (PMID: 33471991). It was observed in 2/34586 chromosomes of the Latino subpopulation in 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 216750). In silico tools suggest the impact of the variant on protein function is benign though these predictions have not been confirmed by functional studies. 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
(Dec 20, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV002039029.2
First in ClinVar: Dec 24, 2021 Last updated: Mar 04, 2023 |
Comment:
Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant does not alter protein … (more)
Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 27443514, 26315354, 24485656, 19609323, 20871615) (less)
|
|
|
Uncertain significance
(Mar 30, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Familial cancer of breast
Affected status: unknown
Allele origin:
unknown
|
Myriad Genetics, Inc.
Accession: SCV004019107.1
First in ClinVar: Jul 29, 2023 Last updated: Jul 29, 2023 |
Comment:
This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
|
|
|
Uncertain significance
(Oct 30, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Familial cancer of breast
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV004201991.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
|
|
|
Uncertain significance
(Mar 22, 2021)
|
no assertion criteria provided
Method: research
|
Chordoma
Affected status: yes
Allele origin:
germline
|
Integrative Tumor Epidemiology Branch, National Institutes of Health
Accession: SCV002549703.1
First in ClinVar: Jul 23, 2022 Last updated: Jul 23, 2022 |
Comment:
Modestly reduce BRCA2 binding, no effect on HRR activity
Number of individuals with the variant: 1
Age: 11-70 years
Ethnicity/Population group: European
|
Comment:
Comment:
The p.I1035V variant (also known as c.3103A>G), located in coding exon 10 of the PALB2 gene, results from an A to G substitution at nucleotide position 3103. The isoleucine at codon 1035 is replaced by valine, an amino acid with highly similar properties. This alteration has been previously detected in a cohort of 381 unselected endometrial cancer patients who underwent multi-gene panel testing (Ring KL et al. Mod. Pathol., 2016 11;29:1381-1389). The alteration was also identified in 1/6385 invasive epithelial ovarian cancer cases and 1/6114 controls of European ancestry (Song H et al. J Med Genet, 2021 05;58:305-313) and in 1/60,466 breast cancer cases and 1/53,461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Comment:
Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 27443514, 26315354, 24485656, 19609323, 20871615)
Comment:
This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
Comment:
Modestly reduce BRCA2 binding, no effect on HRR activity
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 sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1035 of the PALB2 protein (p.Ile1035Val). This variant is present in population databases (no rsID available, gnomAD 0.006%). This missense change has been observed in individual(s) with endometrial cancer, chordoma, and hereditary breast and ovarian cancer (PMID: 27443514, 34284872, 35762214). ClinVar contains an entry for this variant (Variation ID: 216750). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt PALB2 protein function. Experimental studies have shown that this missense change affects PALB2 function (PMID: 35762214). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Comment:
The p.I1035V variant (also known as c.3103A>G), located in coding exon 10 of the PALB2 gene, results from an A to G substitution at nucleotide position 3103. The isoleucine at codon 1035 is replaced by valine, an amino acid with highly similar properties. This alteration has been previously detected in a cohort of 381 unselected endometrial cancer patients who underwent multi-gene panel testing (Ring KL et al. Mod. Pathol., 2016 11;29:1381-1389). The alteration was also identified in 1/6385 invasive epithelial ovarian cancer cases and 1/6114 controls of European ancestry (Song H et al. J Med Genet, 2021 05;58:305-313) and in 1/60,466 breast cancer cases and 1/53,461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Comment:
Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 27443514, 26315354, 24485656, 19609323, 20871615)
Comment:
This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
Comment:
Modestly reduce BRCA2 binding, no effect on HRR activity
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Rare germline variants in PALB2 and BRCA2 in familial and sporadic chordoma. | Xia B | Human mutation | 2022 | PMID: 35762214 |
| Mutational profile of hereditary breast and ovarian cancer - Establishing genetic testing guidelines in a developing country. | Krivokuca A | Current problems in cancer | 2022 | PMID: 34284872 |
| 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 |
| Population-based targeted sequencing of 54 candidate genes identifies PALB2 as a susceptibility gene for high-grade serous ovarian cancer. | Song H | Journal of medical genetics | 2021 | PMID: 32546565 |
| Germline multi-gene hereditary cancer panel testing in an unselected endometrial cancer cohort. | Ring KL | Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc | 2016 | PMID: 27443514 |
| 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 |
Text-mined citations for rs863224783 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Sep 29, 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.