ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.587G>T (p.Ser196Ile) (rs80358818)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000044783 SCV000072796 uncertain significance Hereditary breast and ovarian cancer syndrome 2019-10-17 criteria provided, single submitter clinical testing This sequence change replaces serine with isoleucine at codon 196 of the BRCA2 protein (p.Ser196Ile). The serine residue is highly conserved and there is a large physicochemical difference between serine and isoleucine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals affected with breast cancer, as well as healthy controls (PMID: 21218378, 30287823). ClinVar contains an entry for this variant (Variation ID: 51959). 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 disruptive, but these predictions have not been confirmed by published functional studies. Experimental studies have shown that this variant causes a slight increase in exon 7 skipping (PMID: 23983145), although the impact of this alteration on BRCA2 protein function was not reported. 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 RCV000166163 SCV000216937 uncertain significance Hereditary cancer-predisposing syndrome 2017-01-24 criteria provided, single submitter clinical testing Insufficient or conflicting evidence;In silico models in agreement (deleterious) and/or completely conserved position in appropriate species
Counsyl RCV000113840 SCV000489341 uncertain significance Breast-ovarian cancer, familial 2 2016-09-20 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000780031 SCV000917037 uncertain significance not specified 2019-11-27 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.587G>T (p.Ser196Ile) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251402 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.587G>T has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer. The variant, c.587G>T, has been reported in the literature in several individuals of Japanese ancestry, and was found in both patients affected with breast cancer, and healthy controls (Momozawa 2018). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. At least one publication reports experimental evidence evaluating an impact exon 7 skipping, however, does not allow convincing conclusions about the variant effect (Di Giacomo_2013). Three other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and all of them classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Illumina Clinical Services Laboratory,Illumina RCV000113840 SCV001269107 uncertain significance Breast-ovarian cancer, familial 2 2017-06-13 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Clinical Services Laboratory,Illumina RCV001111542 SCV001269108 uncertain significance Fanconi anemia, complementation group D1 2017-06-13 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Breast Cancer Information Core (BIC) (BRCA2) RCV000113840 SCV000147221 uncertain significance Breast-ovarian cancer, familial 2 2003-12-23 no assertion criteria provided clinical testing

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