Submissions for variant NM_000059.4(BRCA2):c.6403A>C (p.Asn2135His)

gnomAD frequency: 0.00001  dbSNP: rs80358876

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000044933	SCV000072946	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-09-03	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with histidine, which is basic and polar, at codon 2135 of the BRCA2 protein (p.Asn2135His). This variant is present in population databases (rs80358876, gnomAD 0.0009%). This missense change has been observed in individual(s) with breast cancer and epithelial ovarian cancer (PMID: 11241844, 27208206). ClinVar contains an entry for this variant (Variation ID: 52083). 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.
GeneDx	RCV000160110	SCV000210387	uncertain significance	not provided	2015-03-19	criteria provided, single submitter	clinical testing	This variant is denoted BRCA2 c.6403A>C at the cDNA level, p.Asn2135His (N2135H) at the protein level, and results in the change of an Asparagine to a Histidine (AAC>CAC). Using alternate nomenclature, this variant has been previously published as BRCA2 6631A>C. This variant was observed in at least one individual that underwent BRCA2 sequencing (Edwards 2001). BRCA2 Asn2135His was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Asparagine and Histidine differ in some properties, this is considered a semi-conservative amino acid substitution. BRCA2 Asn2135His occurs at a position that is not conserved across species and is not located in a known functional domain (UniProt). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available information, it is unclear whether BRCA2 Asn2135His is pathogenic or benign. We consider it to be a variant of uncertain significance.
Ambry Genetics	RCV000165986	SCV000216744	likely benign	Hereditary cancer-predisposing syndrome	2024-06-05	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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001269229	SCV001448544	uncertain significance	not specified	2020-11-19	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.6403A>C (p.Asn2135His) results in a conservative amino acid change in the encoded protein sequence. Three of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4.2e-06 in 240454 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.6403A>C has been reported in the literature in at least one individual without clinical information (Edwards_2001). This report does not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Color Diagnostics, LLC DBA Color Health	RCV000165986	SCV002052073	uncertain significance	Hereditary cancer-predisposing syndrome	2022-02-08	criteria provided, single submitter	clinical testing	This missense variant replaces asparagine with histidine at codon 2135 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 ovarian cancer and an individual screened for hereditary cancer (PMID: 11241844, 27208206). This variant also has been reported in a multifactorial analysis with co-occurrence and family history likelihood ratios for pathogenicity of 1.0757 and 0.6366, respectively (PMID: 31131967). This variant has been identified in 1/240454 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.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000165986	SCV003852493	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).
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000160110	SCV005624500	uncertain significance	not provided	2024-04-10	criteria provided, single submitter	clinical testing	The BRCA2 c.6403A>C (p.Asn2135His) variant has been reported in the published literature in a woman affected with ovarian cancer (PMID: 27208206 (2016)). The frequency of this variant in the general population, 0.0000042 (1/240454 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 damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
Sharing Clinical Reports Project (SCRP)	RCV000083127	SCV000115201	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2012-05-01	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000083127	SCV000146843	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2004-02-20	no assertion criteria provided	clinical testing