Submissions for variant NM_000059.4(BRCA2):c.9986A>G (p.Asn3329Ser)

gnomAD frequency: 0.00002  dbSNP: rs76635144

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000130425	SCV000185289	likely benign	Hereditary cancer-predisposing syndrome	2018-11-30	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000197376	SCV000254229	likely benign	Hereditary breast ovarian cancer syndrome	2023-12-31	criteria provided, single submitter	clinical testing
GeneDx	RCV001704055	SCV000518147	likely benign	not provided	2021-06-06	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 21952622)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001704055	SCV000600886	uncertain significance	not provided	2022-06-04	criteria provided, single submitter	clinical testing	In the published literature, this variant has been reported in individuals with breast cancer (PMID: 35264596 (2022)), ovarian cancer (PMID: 34157791 (2021)), prostate cancer (PMID: 21952622 (2011)), and esophageal squamous cell carcinoma (PMID: 31396961 (2020)). This variant has also been reported in unaffected individuals (PMID: 32467295 (2020), 33471991 (2021), see also LOVD (https://databases.lovd.nl/shared/variants/BRCA2)). The frequency of this variant in the general population, 0.000024 (6/250776 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 predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.
Color Diagnostics, LLC DBA Color Health	RCV000130425	SCV000903016	likely benign	Hereditary cancer-predisposing syndrome	2015-12-08	criteria provided, single submitter	clinical testing
Mendelics	RCV000989093	SCV001139282	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2023-08-22	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000425781	SCV001361748	likely benign	not specified	2024-08-05	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.9986A>G (p.Asn3329Ser) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 250776 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. This variant has been observed in at-least one woman in a database of women who are cancer free and older than age 70 (FLOSSIES database). c.9986A>G has been reported in the literature in at-least one individual affected with prostate cancer (example, Kote-Jarai_2011), one individual affected with breast cancer (example, Guindalini_2022) and as a VUS in one family undergoing testing for the BRCA1/2 genes (example, Zuntini_2018). However, these report(s) 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 at our laboratory (BRCA2 c.1755_1759delGAAAA, p.Lys585fsX3), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 21952622, 30254663, 35264596). ClinVar contains an entry for this variant (Variation ID: 141780). Based on the evidence outlined above, the variant was classified as likely benign.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001704055	SCV001477524	uncertain significance	not provided	2020-06-08	criteria provided, single submitter	clinical testing	The BRCA2 c.9986A>G; p.Asn3329Ser variant (rs76635144) is reported in the literature in a family affected with breast or ovarian cancer, but without clear evidence for disease association (Zuntini 2018). This variant is reported in ClinVar (Variation ID: 141780), and is only observed on six alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. The asparagine at codon 3329 is weakly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. Due to limited information, the clinical significance of the p.Asn3329Ser variant is uncertain at this time. References: Zuntini R et al. Dealing With BRCA1/2 Unclassified Variants in a Cancer Genetics Clinic: Does Cosegregation Analysis Help?. Front Genet. 2018;9:378.
Sema4, Sema4	RCV000130425	SCV002532076	uncertain significance	Hereditary cancer-predisposing syndrome	2021-09-18	criteria provided, single submitter	curation
All of Us Research Program, National Institutes of Health	RCV000989093	SCV004846253	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2023-11-30	criteria provided, single submitter	clinical testing
Department of Medical and Surgical Sciences, University of Bologna	RCV000989093	SCV004228308	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2023-09-01	no assertion criteria provided	clinical testing	BP1(Strong) according to ACMG/AMP classification guidelines specified for BRCA1 & BRCA2 (Classification Criteria V1.0.0 2023-09-08 - https://cspec.genome.network/cspec/ui/svi/affiliation/50087) (PMID: 38160042)
PreventionGenetics, part of Exact Sciences	RCV004724827	SCV005337402	uncertain significance	BRCA2-related disorder	2024-07-22	no assertion criteria provided	clinical testing	The BRCA2 c.9986A>G variant is predicted to result in the amino acid substitution p.Asn3329Ser. This variant has been reported in an individual with breast cancer (Guindalini et al. 2022. PubMed ID: 35264596), in an individual with biliary tract cancer (Okawa et al. 2022. PubMed ID: 36243179), and in an individual with prostate cancer (Kote-Jarai et al. 2011. PubMed ID: 21952622). This variant is not predicted to alter splicing based on available splicing prediction programs (Alamut Visual v1.6.1). However, the use of computer prediction programs is not equivalent to functional evidence. In addition, this variant has been reported in two individuals in healthy control cohorts (Breast Cancer Association Consortium et al. 2021. PubMed ID: 33471991; Dong et al. 2020. PubMed ID: 32467295). This variant is reported in 0.0065% of alleles in individuals of South Asian descent in gnomAD. It has conflicting classifications listed in ClinVar ranging from benign to uncertain significance (https://www.ncbi.nlm.nih.gov/clinvar/variation/141780/). Although this variant may be suspected benign, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.