ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.865A>G (p.Asn289Asp) (rs766173)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000164485 SCV000215132 likely benign Hereditary cancer-predisposing syndrome 2017-01-16 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: In silico models in agreement (benign),Co-occurence with mutation in same gene (phase unknown)
Breast Cancer Information Core (BIC) (BRCA2) RCV000031759 SCV000145782 uncertain significance Breast-ovarian cancer, familial 2 2002-05-29 no assertion criteria provided clinical testing
Color RCV000164485 SCV000683990 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-30 criteria provided, single submitter clinical testing
Counsyl RCV000031759 SCV000488144 uncertain significance Breast-ovarian cancer, familial 2 2016-02-19 criteria provided, single submitter clinical testing
GeneDx RCV000441052 SCV000512335 likely benign not specified 2016-11-08 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Integrated Genetics/Laboratory Corporation of America RCV000589996 SCV000695170 likely benign not provided 2016-08-22 criteria provided, single submitter clinical testing Variant summary: The BRCA2 c.865A>G (p.Asn289Asp) variant involves the alteration of a not conserved nucleotide. 3/5 in silico tools predict a benign outcome for this variant. This variant was found in 25/120576 control chromosomes at a frequency of 0.0002073, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA2 variant (0.0007503). However, the variant has been observed in a family listed in kConFab database in which it co-occurred with another pathogenic BRCA2 variant (p.Ser1955X) and in two internal LCA samples, where it co-occurred with the same (p.Ser1955X) pathogenic BRCA2 variant. These co-occurrences suggest that in these individuals the variant either resides in cis with the pathogenic BRCA2 variant and is a passenger SNP or, if the variant resides in trans with the pathogenic BRCA2 variant than the c.865A>G is benign because otherwise these patients would have presented with Fanconi anemia. The variant of interest has been observed in HBOC spectrum patients however, due to limited co-segregation and phenotypic information these observations do not permit establishment of a cause-effect relationship between the variant and HBOC. Furthermore, a publication (Cunningham_2014) and a reputable clinical diagnostic laboratory classify the variant as "polymorphic/likely benign; three other clinical labs classified this variant as VUS, all without evidence to independently evaluate. Considering all evidences, this variant was classified as a probably benign until additional information becomes available.
Invitae RCV000045592 SCV000073605 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-12-22 criteria provided, single submitter clinical testing This sequence change replaces asparagine with aspartic acid at codon 289 of the BRCA2 protein (p.Asn289Asp). The asparagine residue is moderately conserved and there is a small physicochemical difference between asparagine and aspartic acid. This variant is present in population databases (rs766173, ExAC 0.002%). This variant has been reported in individuals affected with breast cancer (PMID: 25896959, 24853695), and in individuals in the Breast Cancer Information Core database (PMID: 10923033). However, in several individuals a pathogenic variant (c.5864C>A, p.Ser1955*) was identified in the BRCA2 gene, which suggests that the c.865A>G substitution in BRCA2 was not the primary cause of disease in these cases. This variant is also known as 1093A>G in the literature. ClinVar contains an entry for this variant (Variation ID: 38176). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic RCV000589996 SCV000778638 uncertain significance not provided 2017-12-20 no assertion criteria provided clinical testing
Sharing Clinical Reports Project (SCRP) RCV000031759 SCV000054367 uncertain significance Breast-ovarian cancer, familial 2 2008-07-02 no assertion criteria provided clinical testing

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