ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.7865A>G (p.Asn2622Ser) (rs142899125)

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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 RCV000130086 SCV000184914 uncertain significance Hereditary cancer-predisposing syndrome 2018-11-06 criteria provided, single submitter clinical testing Insufficient evidence
GeneDx RCV000656802 SCV000210450 uncertain significance not provided 2017-07-03 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.7865A>G at the cDNA level, p.Asn2622Ser (N2622S) 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 8093A>G. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Asn2622Ser was observed at an allele frequency of 0.06% (7/10,354) in individuals of African ancestry in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Asparagine and Serine share similar properties, this is considered a conservative amino acid substitution. BRCA2 Asn2622Ser occurs at a position that is conserved across species and is located in the DNA binding domain (Yang 2002). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether BRCA2 Asn2622Ser is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000656802 SCV000226550 uncertain significance not provided 2014-07-16 criteria provided, single submitter clinical testing
Invitae RCV000197898 SCV000254215 uncertain significance Hereditary breast and ovarian cancer syndrome 2019-12-23 criteria provided, single submitter clinical testing This sequence change replaces asparagine with serine at codon 2622 of the BRCA2 protein (p.Asn2622Ser). The asparagine residue is highly conserved and there is a small physicochemical difference between asparagine and serine. This variant is present in population databases (rs142899125, ExAC 0.07%). This variant has been reported in an individual affected with breast cancer (PMID: 25186627). ClinVar contains an entry for this variant (Variation ID: 91496). Experimental studies have shown that this missense change reduces homology-directed repair (HDR) activity of the BRCA2 protein (PMID: 29884841). 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. 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.
Michigan Medical Genetics Laboratories,University of Michigan RCV000077013 SCV000267812 uncertain significance Breast-ovarian cancer, familial 2 2016-04-21 criteria provided, single submitter clinical testing
Counsyl RCV000077013 SCV000786046 uncertain significance Breast-ovarian cancer, familial 2 2018-02-16 criteria provided, single submitter clinical testing
Color RCV000130086 SCV000905023 uncertain significance Hereditary cancer-predisposing syndrome 2020-03-05 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV001194386 SCV001363892 uncertain significance not specified 2019-06-25 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.7865A>G (p.Asn2622Ser) results in a conservative amino acid change located in the helical domain (IPR015252) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 2.8e-05 in 251260 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The variant, c.7865A>G, has been reported in the literature in an individual affected with breast cancer (Tung_2014). However, this report does not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. Co-occurrence with another pathogenic variant has been reported (BRCA1 c.5324T>G, p.Met1775Arg) for this variant, providing supporting evidence for a benign role (internal data). At least one publication reports experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect (Hart_2019). Six submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance until additional evidence becomes available.
Sharing Clinical Reports Project (SCRP) RCV000077013 SCV000108810 likely pathogenic Breast-ovarian cancer, familial 2 2013-01-10 no assertion criteria provided clinical testing

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