Submissions for variant NM_000059.4(BRCA2):c.4856A>G (p.Asn1619Ser)

dbSNP: rs80358709

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000113352	SCV000786349	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2018-04-18	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000773266	SCV000906914	uncertain significance	Hereditary cancer-predisposing syndrome	2023-06-01	criteria provided, single submitter	clinical testing	This missense variant replaces asparagine with serine at codon 1619 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 a multifactorial analysis with co-occurrence and family history likelihood ratios for pathogenicity of f 1.025 and 0.473, respectively (PMID: 31131967). This variant has not been identified 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	RCV000781110	SCV000918948	uncertain significance	not specified	2018-08-24	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.4856A>G (p.Asn1619Ser) results in a conservative amino acid change in the encoded protein sequence. Four of four in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 245428 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.4856A>G in individuals affected with Hereditary Breast and Ovarian Cancer and no experimental evidence demonstrating its impact on protein function have been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Ambry Genetics	RCV000773266	SCV001184986	uncertain significance	Hereditary cancer-predisposing syndrome	2021-05-17	criteria provided, single submitter	clinical testing	The p.N1619S variant (also known as c.4856A>G), located in coding exon 10 of the BRCA2 gene, results from an A to G substitution at nucleotide position 4856. The asparagine at codon 1619 is replaced by serine, an amino acid with highly similar properties. This amino acid position is poorly 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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001558036	SCV001472821	uncertain significance	not provided	2020-07-29	criteria provided, single submitter	clinical testing	The BRCA2 c.4856A>G; p.Asn1619Ser variant (rs80358709), to our knowledge, is not reported in the medical literature associated with disease but is considered likely benign by a multifactorial likelihood analysis (Parsons 2019). This variant is reported in ClinVar (Variation ID: 51729), and is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The asparagine at codon 1619 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.Asn1619Ser variant is uncertain at this time. References: Parsons MT et al. Large scale multifactorial likelihood quantitative analysis of BRCA1 and BRCA2 variants: An ENIGMA resource to support clinical variant classification. Hum Mutat. 2019;40(9):1557-1578.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001313202	SCV001503686	uncertain significance	Hereditary breast ovarian cancer syndrome	2023-04-10	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 51729). 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. 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 BRCA2 protein function. This missense change has been observed in individual(s) with breast cancer (PMID: 10923033). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 1619 of the BRCA2 protein (p.Asn1619Ser).
GeneDx	RCV001558036	SCV001779904	likely benign	not provided	2019-04-19	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (Lek et al., 2016)
University of Washington Department of Laboratory Medicine, University of Washington	RCV000773266	SCV003852150	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	RCV000113352	SCV004845740	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2023-06-26	criteria provided, single submitter	clinical testing	This missense variant replaces asparagine with serine at codon 1619 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 a multifactorial analysis with co-occurrence and family history likelihood ratios for pathogenicity of f 1.025 and 0.473, respectively (PMID: 31131967). This variant has not been identified 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.
Breast Cancer Information Core (BIC) (BRCA2)	RCV000113352	SCV000146495	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004537195	SCV004718875	uncertain significance	BRCA2-related disorder	2024-08-02	no assertion criteria provided	clinical testing	The BRCA2 c.4856A>G variant is predicted to result in the amino acid substitution p.Asn1619Ser. This variant has been reported in the literature in an individual with breast cancer (Szabo C et al. 2000. PubMed ID: 10923033). This variant is not present in a large population database, indicating this variant is rare. This variant has conflicting interpretations in ClinVar ranging from uncertain to likely benign (https://www.ncbi.nlm.nih.gov/clinvar/variation/51729/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.