Submissions for variant NM_000059.4(BRCA2):c.1709A>G (p.Asn570Ser)

dbSNP: rs431825284

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000767150	SCV000566304	uncertain significance	not provided	2018-06-04	criteria provided, single submitter	clinical testing	This variant is denoted BRCA2 c.1709A>G at the cDNA level, p.Asn570Ser (N570S) at the protein level, and results in the change of an Asparagine to a Serine (AAT>AGT). Using alternate nomenclature, this variant would be defined as BRCA2 1937A>G. This variant has been reported in at least one individual with breast cancer (Briceno-Balcazar 2017). BRCA2 Asn570Ser was not observed in large population cohorts (Lek 2016). This variant is not located in a known functional domain. In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether BRCA2 Asn570Ser is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000637388	SCV000758844	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-11-14	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 570 of the BRCA2 protein (p.Asn570Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast cancer (PMID: 29021639). ClinVar contains an entry for this variant (Variation ID: 96768). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt BRCA2 protein function with a negative predictive value of 95%. 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.
Ambry Genetics	RCV001012835	SCV001173337	uncertain significance	Hereditary cancer-predisposing syndrome	2024-02-23	criteria provided, single submitter	clinical testing	The p.N570S variant (also known as c.1709A>G), located in coding exon 9 of the BRCA2 gene, results from an A to G substitution at nucleotide position 1709. The asparagine at codon 570 is replaced by serine, an amino acid with highly similar properties. This alteration has been reported in a cohort of 853 individual referred for BRCA1 and BRCA2 testing (Briceño-Balcázar I et al. Colomb. Med., 2017 Jun;48:58-63). 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000767150	SCV001470202	uncertain significance	not provided	2020-01-16	criteria provided, single submitter	clinical testing
University of Washington Department of Laboratory Medicine, University of Washington	RCV001012835	SCV003851585	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).
Mayo Clinic Laboratories, Mayo Clinic	RCV000767150	SCV004226419	uncertain significance	not provided	2022-04-14	criteria provided, single submitter	clinical testing	BP4, PM2
Color Diagnostics, LLC DBA Color Health	RCV001012835	SCV004361234	uncertain significance	Hereditary cancer-predisposing syndrome	2021-10-11	criteria provided, single submitter	clinical testing	This missense variant replaces asparagine with serine at codon 570 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 an individual affected with breast cancer (PMID: 29021639) and in a breast cancer case-control meta-analysis in 1/53460 unaffected individuals and absent in 60466 cases (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_005818). 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.
Sharing Clinical Reports Project (SCRP)	RCV000082889	SCV000114963	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2010-04-28	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000082889	SCV000591761	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2		no assertion criteria provided	clinical testing	The p.Asn570Ser variant was not identified in the literature nor was it identified in the BIC, LOVD, UMD, Google, Cosmic, HGMD databases.The variant was identified in ClinVar and was classified as an uncertain variant by the Sharing Clinical Reports Project (SCRP) (submitted within the ClinVar database and derived from Myriad reports). The p.Asn570 residue is not conserved in mammals and computational analyses (SIFT, AlignGVGD, BLOSUM) do not suggest a high likelihood of impact to the protein. However, this information is not predictive enough to rule out pathogenicity. In addition, in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a signifcant 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.