ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.240A>G (p.Ile80Met) (rs80358505)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000043985 SCV000071998 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-12-10 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with methionine at codon 80 of the BRCA2 protein (p.Ile80Met). The isoleucine residue is moderately conserved and there is a small physicochemical difference between isoleucine and methionine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual in the Breast Cancer Information Core database (PMID: 10923033). However, in that individual a pathogenic allele was also identified in BRCA2, which suggests that this c.240A>G variant was not the primary cause of disease. ClinVar contains an entry for this variant (Variation ID: 51277). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0". The methionine 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. 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.
Ambry Genetics RCV000130843 SCV000185741 uncertain significance Hereditary cancer-predisposing syndrome 2016-01-21 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence,In silico models in agreement (benign)
Color RCV000130843 SCV000688752 uncertain significance Hereditary cancer-predisposing syndrome 2018-09-25 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000781151 SCV000919021 uncertain significance not specified 2018-10-22 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.240A>G (p.Ile80Met) 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 246180 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.240A>G. has been reported in the literature in at least one individual affected with head and neck squamous cell carcinoma (Chandrasekharappa_2017). This report does not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. Co-occurrences with other pathogenic variants have been reported (BRCA1 c.3839_3843delinsAGGC, p.Ser1280X; BRCA2 c.3599_3600delGT, p.Cys1200Terfs), providing supporting evidence for a benign role. 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 VUS-possibly benign.
Breast Cancer Information Core (BIC) (BRCA2) RCV000113305 SCV000146426 uncertain significance Breast-ovarian cancer, familial 2 2003-12-23 no assertion criteria provided clinical testing

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