NM_024675.4(PALB2):c.3296C>G (p.Thr1099Arg) AND not provided

Germline classification:: Uncertain significance (4 submissions)
Last evaluated:: Oct 4, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000657014.15

Allele description [Variation Report for NM_024675.4(PALB2):c.3296C>G (p.Thr1099Arg)]

NM_024675.4(PALB2):c.3296C>G (p.Thr1099Arg)

Gene:

PALB2:partner and localizer of BRCA2 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

16p12.2

Genomic location:

Preferred name:

NM_024675.4(PALB2):c.3296C>G (p.Thr1099Arg)

HGVS:

NC_000016.10:g.23607918G>C
NG_007406.1:g.38440C>G
NM_024675.4:c.3296C>GMANE SELECT
NP_078951.2:p.Thr1099Arg
NP_078951.2:p.Thr1099Arg
LRG_308t1:c.3296C>G
LRG_308:g.38440C>G
LRG_308p1:p.Thr1099Arg
NC_000016.9:g.23619239G>C
NM_024675.3:c.3296C>G
p.T1099R

Protein change:

T1099R

Links:

dbSNP: rs142132127

NCBI 1000 Genomes Browser:

rs142132127

Molecular consequence:

NM_024675.4:c.3296C>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000292841	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Uncertain significance (Oct 4, 2024)	germline	clinical testing	Citation Link,
SCV000807106	PreventionGenetics, part of Exact Sciences	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Nov 29, 2017)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001134551	Quest Diagnostics Nichols Institute San Juan Capistrano	criteria provided, single submitter (Quest Diagnostics criteria)	Uncertain significance (Aug 12, 2023)	unknown	clinical testing	PubMed (10) [See all records that cite these PMIDs] 30883245, 31422574, 31428572, 31636395, 33471991, 35402282, 25186627, 26315354, 26976419, 26467025
SCV005194279	Breakthrough Genomics, Breakthrough Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance	germline	not provided	PubMed (1) [See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing, not provided
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Deleterious Germline Mutations Are a Risk Factor for Neoplastic Progression Among High-Risk Individuals Undergoing Pancreatic Surveillance.

Abe T, Blackford AL, Tamura K, Ford M, McCormick P, Chuidian M, Almario JA, Borges M, Lennon AM, Shin EJ, Klein AP, Hruban RH, Canto MI, Goggins M.

J Clin Oncol. 2019 May 1;37(13):1070-1080. doi: 10.1200/JCO.18.01512. Epub 2019 Mar 18.

PubMed [citation]

PMID:: 30883245
PMCID:: PMC6494358

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, Azzarello-Burri S, Steindl K, Boonsawat P, Zweier M, Dedes KJ, Joset P, Fink D, Rauch A.

Swiss Med Wkly. 2019 Aug 12;149:w20092. doi: 10.4414/smw.2019.20092.

PubMed [citation]

PMID:: 31422574

See all PubMed Citations (11)

Details of each submission

From GeneDx, SCV000292841.15

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

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)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From PreventionGenetics, part of Exact Sciences, SCV000807106.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Quest Diagnostics Nichols Institute San Juan Capistrano, SCV001134551.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (10)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Breakthrough Genomics, Breakthrough Genomics, SCV005194279.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	not provided	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Oct 20, 2024

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