Submissions for variant NM_000059.4(BRCA2):c.1409A>C (p.Glu470Ala)

gnomAD frequency: 0.00002  dbSNP: rs750341436

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000220996	SCV000278360	likely benign	Hereditary cancer-predisposing syndrome	2021-06-28	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.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000499995	SCV000591743	uncertain significance	not specified	2015-06-10	criteria provided, single submitter	clinical testing
GeneDx	RCV000657040	SCV000617104	uncertain significance	not provided	2017-11-14	criteria provided, single submitter	clinical testing	This variant is denoted BRCA2 c.1409A>C at the cDNA level, p.Glu470Ala (E470A) at the protein level, and results in the change of a Glutamic Acid to an Alanine (GAA>GCA). Using alternate nomenclature, this variant would be defined as BRCA2 1637A>C. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Glu470Ala was not observed at a significant frequency in large population cohorts (Lek 2016). Since Glutamic Acid and Alanine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA2 Glu470Ala is not located in a known functional domain. In-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. Based on currently available information, it is unclear whether BRCA2 Glu470Ala is pathogenic or benign. We consider it to be a variant of uncertain significance.
Color Diagnostics, LLC DBA Color Health	RCV000220996	SCV000683422	uncertain significance	Hereditary cancer-predisposing syndrome	2019-11-20	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with alanine at codon 470 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 2/247704 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	RCV000757932	SCV000886458	benign	Hereditary breast ovarian cancer syndrome	2018-09-28	criteria provided, single submitter	research	The BRCA2 variant designated as NM_000059.3(BRCA2):c.1409A>C (p.Glu470Ala) is classified as benign. Computer software programs predict that this variant is likely to be tolerated, adding supporting evidence that this variant is benign. This variant is found in exon 10, in a domain where non-truncating mutations are usually benign. Co-segregation analysis of one observed family was performed using analyze.myvariant.org (Rañola et al, 2018, PMID:28965303) and demonstrates that this allele has a likelihood ratio of pathogenicity of 0.0004 to 1 (Thompson et al, 2003, PMID:2900794), providing additional evidence that this variant is less likely to cause cancer. Bayesian analysis integrating all of this data (Tavtigian et al, 2018, Tavtigian et al, 2018, PMID:29300386) gives less than 1% probability of pathogenicity, which is consistent with a classification of benign. This variant is not predicted to alter BRCA2 function or modify cancer risk. This analysis was performed in conjunction with the family studies project as part of the University of Washington Find My Variant Study.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000757932	SCV000953462	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-08-05	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with alanine, which is neutral and non-polar, at codon 470 of the BRCA2 protein (p.Glu470Ala). This variant is present in population databases (rs750341436, gnomAD 0.003%). This missense change has been observed in individual(s) with uterine cancer (PMID: 30374176). ClinVar contains an entry for this variant (Variation ID: 233895). 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 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000499995	SCV001363144	uncertain significance	not specified	2019-08-23	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.1409A>C (p.Glu470Ala) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8.1e-06 in 247704 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.1409A>C in individuals affected with affected with Hereditary Breast and Ovarian Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Six ClinVar submissions (evaluation after 2014) classified this variant as VUS (5x) and benign (1x). Based on the evidence outlined above, the variant was classified as uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000657040	SCV001469662	uncertain significance	not provided	2020-02-04	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798723	SCV002042440	uncertain significance	Breast and/or ovarian cancer	2020-04-15	criteria provided, single submitter	clinical testing
University of Washington Department of Laboratory Medicine, University of Washington	RCV000220996	SCV003851365	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	RCV003998586	SCV004846917	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2023-08-15	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with alanine at codon 470 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 2/247704 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.
GenomeConnect, ClinGen	RCV000657040	SCV001338880	not provided	not provided		no assertion provided	phenotyping only	Variant interpretted as Uncertain significance and reported on 02-13-2018 by Lab or GTR ID 505849. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.