Submissions for variant NM_000059.4(BRCA2):c.4213A>G (p.Asn1405Asp)

dbSNP: rs1555283633

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001821711	SCV000694751	uncertain significance	not specified	2025-02-24	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.4213A>G (p.Asn1405Asp) 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 was absent in 236124 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.4213A>G has been reported in the literature in an individual affected with pancreatic cancer as well as an unaffected control (Mizukami_2020). 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. The following publication has been ascertained in the context of this evaluation (PMID: 32980694). ClinVar contains an entry for this variant (Variation ID: 495458). Based on the evidence outlined above, the variant was classified as uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001042617	SCV001206313	uncertain significance	Hereditary breast ovarian cancer syndrome	2019-12-22	criteria provided, single submitter	clinical testing	This variant has been reported in individuals in the Leiden Open-source Variation Database (PMID: 21520333). ClinVar contains an entry for this variant (Variation ID: 495458). This variant is not present in population databases (ExAC no frequency). This sequence change replaces asparagine with aspartic acid at codon 1405 of the BRCA2 protein (p.Asn1405Asp). The asparagine residue is weakly conserved and there is a small physicochemical difference between asparagine and aspartic acid. 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The aspartic acid amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain.
Genetic Services Laboratory, University of Chicago	RCV001821711	SCV002067155	uncertain significance	not specified	2018-06-22	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002331002	SCV002629503	likely benign	Hereditary cancer-predisposing syndrome	2023-11-22	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.
University of Washington Department of Laboratory Medicine, University of Washington	RCV002331002	SCV003848770	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).
GeneDx	RCV000587921	SCV005327575	uncertain significance	not provided	2023-05-30	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Also known as 4441A>G; Observed in cases and controls in a pancreatic cancer study, but was not observed in any cases in a breast cancer case-control study (Momozawa et al., 2018; Mizukami et al., 2020); This variant is associated with the following publications: (PMID: 31911673, 30287823, 32980694)