ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.2918C>T (p.Ser973Leu) (rs397507296)

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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 RCV000165120 SCV000215830 uncertain significance Hereditary cancer-predisposing syndrome 2018-02-14 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 RCV000165120 SCV000911358 likely benign Hereditary cancer-predisposing syndrome 2016-07-25 criteria provided, single submitter clinical testing
Fulgent Genetics RCV000031388 SCV000575760 uncertain significance Breast-ovarian cancer, familial 2 2016-02-22 criteria provided, single submitter clinical testing
GeneDx RCV000220429 SCV000278843 uncertain significance not provided 2018-09-28 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.2918C>T at the cDNA level, p.Ser973Leu (S973L) at the protein level, and results in the change of a Serine to a Leucine (TCG>TTG). This variant, also known as BRCA2 3146C>T using alternate nomenclature, has been observed in at least one individual with breast cancer (Ahmad 2012). BRCA2 Ser973Leu was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is not located in a known functional domain. In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether BRCA2 Ser973Leu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000781108 SCV000918944 uncertain significance not specified 2018-08-24 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.2918C>T (p.Ser973Leu) results in a non-conservative amino acid change in the encoded protein sequence. Three of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.1e-06 in 243890 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2918C>T has been reported in the literature in an individual affected with Hereditary Breast and Ovarian Cancer (Ahmad_2012). This report does not provide an unequivocal conclusion about association of the variant with Hereditary Breast and Ovarian Cancer. A clinical lab via ClinVar has reported one patient who also carries an unspecified pathogenic BRCA1 mutation, suggesting the benign role of the variant of interest. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five ClinVar submissions from other clinical diagnostic laboratories (evaluation after 2014) cites the variant as "uncertain significance." Based on the evidence outlined above, the variant was classified as uncertain significance.
Invitae RCV000471898 SCV000549482 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-06-20 criteria provided, single submitter clinical testing This sequence change replaces serine with leucine at codon 973 of the BRCA2 protein (p.Ser973Leu). The serine residue is weakly conserved and there is a large physicochemical difference between serine and leucine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual affected with breast cancer (PMID: 22486713). This variant has also been observed in an additional individual with breast cancer (Invitae). However, in that individual, a pathogenic allele was also identified in BRCA1, which suggests that this c.2918C>T variant was not the primary cause of disease. ClinVar contains an entry for this variant (Variation ID: 37807). 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.
Mendelics RCV000471898 SCV000838780 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-07-02 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000031388 SCV000296500 uncertain significance Breast-ovarian cancer, familial 2 2016-05-28 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000031388 SCV000053993 uncertain significance Breast-ovarian cancer, familial 2 2008-11-26 no assertion criteria provided clinical testing

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