Submissions for variant NM_000059.4(BRCA2):c.323A>G (p.Asn108Ser)

gnomAD frequency: 0.00003  dbSNP: rs80358568

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000166938	SCV000217758	likely benign	Hereditary cancer-predisposing syndrome	2021-09-30	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	RCV000221445	SCV000279279	uncertain significance	not provided	2023-05-09	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Also known as 551A>G; This variant is associated with the following publications: (PMID: 21702907, 24817641, 32467295, 30606148)
Illumina Laboratory Services, Illumina	RCV000315720	SCV000383610	uncertain significance	Fanconi anemia complementation group D1	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Laboratory Services, Illumina	RCV000077298	SCV000383611	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Counsyl	RCV000077298	SCV000488230	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2016-02-08	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000166938	SCV000683538	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-21	criteria provided, single submitter	clinical testing	This missense variant replaces asparagine with serine at codon 108 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 one individual each affected with breast cancer, ovarian cancer and ductal carcinoma in situ (PMID: 10755399, 28338653, 30606148) and a suspected HBOC family (PMID: 21702907). In a large breast cancer case-control meta-analysis conducted by the BRIDGES consortium, this variant was reported in 5/60466 cases and 2/53461 unaffected controls (p-value=0.459) (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_007696). This variant has been identified in 8/250556 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001372390	SCV001569039	likely benign	Hereditary breast ovarian cancer syndrome	2025-01-13	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000221445	SCV002046325	uncertain significance	not provided	2024-07-26	criteria provided, single submitter	clinical testing	The BRCA2 c.323A>G (p.Asn108Ser) variant has been reported in the published literature in individuals/families with history of breast and/or ovarian cancer (PMID: 35918668 (2022), 30606148 (2019), 28338653 (2017), 10755399 (2000)). In a large scale breast cancer association study, the variant was observed individuals with breast cancer, as well as in reportedly healthy individuals (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/BRCA2)). The frequency of this variant in the general population, 0.00044 (8/18378 chromosomes in East Asian subpopulation (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is higher than would generally be expected for pathogenic variants in this gene. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV002267810	SCV002550245	uncertain significance	not specified	2025-03-04	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV002250509	SCV004211915	uncertain significance	Familial cancer of breast	2023-10-02	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000077298	SCV004846761	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2023-12-01	criteria provided, single submitter	clinical testing	This missense variant replaces asparagine with serine at codon 108 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 one individual each affected with breast cancer, ovarian cancer and ductal carcinoma in situ (PMID: 10755399, 28338653, 30606148) and a suspected HBOC family (PMID: 21702907). In a large breast cancer case-control meta-analysis conducted by the BRIDGES consortium, this variant was reported in 5/60466 cases and 2/53461 unaffected controls (p-value=0.459) (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_007696). This variant has been identified in 8/250556 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.
Fulgent Genetics, Fulgent Genetics	RCV005007965	SCV005634390	uncertain significance	Familial cancer of breast; Breast-ovarian cancer, familial, susceptibility to, 2; Fanconi anemia complementation group D1; Medulloblastoma; Wilms tumor 1; Pancreatic cancer, susceptibility to, 2; Glioma susceptibility 3; Familial prostate cancer	2024-02-18	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000077298	SCV000109095	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2013-10-07	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000077298	SCV000146593	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	1998-06-22	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001356621	SCV001551839	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BRCA2 p.Asn108Ser variant was not identified in the literature. The variant was identified in dbSNP (ID: rs80358568) “With uncertain significance allele”, Exome Aggregation Consortium (ExAC) database, the ClinVar database (classified as a uncertain significance variant by the Sharing Clinical Reports Project, derived from Myriad reports; BIC and Ambry Genetics) and the BIC database (2X with unknown clinical importance). This variant was identified in the Exome Aggregation Consortium (ExAC) database (released Oct 20th, 2014) in 3 of 8278 chromosomes (frequency: 0.0004) from a population of East Asian individuals, although this low number of observations and low frequency is not substantive enough to determine the prevalence of the variant in the general population and its relationship to disease. The p.Asn108Ser residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein. However, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and one of five in-silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predicted a difference in splicing. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of unknown significance.
Center for Precision Medicine, Meizhou People's Hospital	RCV002250509	SCV002520925	uncertain significance	Familial cancer of breast		no assertion criteria provided	literature only