Submissions for variant NM_000059.4(BRCA2):c.841G>A (p.Asp281Asn)

gnomAD frequency: 0.00007  dbSNP: rs80359088

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001081452	SCV000073525	likely benign	Hereditary breast ovarian cancer syndrome	2025-01-06	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000130406	SCV000185267	likely benign	Hereditary cancer-predisposing syndrome	2021-11-26	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
GeneDx	RCV000586972	SCV000566347	likely benign	not provided	2018-09-28	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 26689913, 29126202, 29338080, 28767289)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000586972	SCV000600802	uncertain significance	not provided	2023-01-05	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.00038 (6/15988 chromosomes in African/African American subpopulation, http://gnomad.broadinstitute.org), is higher than would generally be expected for pathogenic variants in this gene. In the published literature, it has been reported in individuals with pancreatic cancer (PMIDs: 28767289 (2017), 29338080 (2018), 32659497 (2020)), breast cancer (PMID: 34196900 (2021)), and lung cancer (PMIDs: 26689913 (2015) and 28843361 (2017)). 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.
Color Diagnostics, LLC DBA Color Health	RCV000130406	SCV000683965	uncertain significance	Hereditary cancer-predisposing syndrome	2022-12-19	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with asparagine at codon 281 of the BRCA2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with pancreatic adenocarcinoma (PMID: 28767289, 29338080, 32659497), breast cancer (DOI: 10.1101/2020.08.09.20171165 ), and lung cancer (PMID: 28843361). This variant has been reported in a multifactorial analysis as likely benign based in part to segregation and family history likelihood ratios (PMID: 31131967). This variant has been identified in 6/243274 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000482899	SCV000695151	likely benign	not specified	2023-04-17	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.841G>A (p.Asp281Asn) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. A recent report from the CAGI5 (fifth Critical Assessment of Genome Interpretation) challenge has classified this variant as likely benign in a prediction protocol that includes assessment of the impact of this variant on splicing and protein function using four sets of predictors (Padilla_2019). The variant allele was found at a frequency of 2.5e-05 in 243274 control chromosomes (gnomAD). At least 3 control individuals in gnomAD are above the average age of onset for HBOC (i.e. >50 years). In addition, this variant was found in 3/2559 (0.0012) African American individuals who are older than 70 years and cancer free (FLOSSIES database). c.841G>A has been reported in the literature as a VUS in individuals affected with lung cancer or pancreatic cancer within the TGCA cohort and in settings of multigene cancer panel testing (example, Lu_2015, Shindo_2017, Parry_2017, O'Reilly_2018_Ren_2021). 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 reported in the BIC database (reported as BRCA1 c.4611_4612insG, p.Gln1537_Gln1538?fs), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Multiple clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (likely benign, n=4; VUS, n=4). Some submitters cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was re-classified as likely benign.
Sema4, Sema4	RCV000130406	SCV002531943	uncertain significance	Hereditary cancer-predisposing syndrome	2021-08-02	criteria provided, single submitter	curation
University of Washington Department of Laboratory Medicine, University of Washington	RCV000130406	SCV003848071	likely benign	Hereditary cancer-predisposing syndrome	2023-03-23	criteria provided, single submitter	curation	Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673).
All of Us Research Program, National Institutes of Health	RCV004803912	SCV004846830	uncertain significance	BRCA2-related cancer predisposition	2024-09-23	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with asparagine at codon 281 of the BRCA2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with pancreatic adenocarcinoma (PMID: 28767289, 29338080, 32659497), breast cancer (DOI: 10.1101/2020.08.09.20171165 ), and lung cancer (PMID: 28843361). This variant has been reported in a multifactorial analysis as likely benign based in part to segregation and family history likelihood ratios (PMID: 31131967). This variant has been identified in 6/243274 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.
Sharing Clinical Reports Project (SCRP)	RCV000077438	SCV000109236	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2012-03-29	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000077438	SCV000145778	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2002-06-20	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004732629	SCV000805779	likely benign	BRCA2-related disorder	2024-08-26	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).