ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.692C>T (p.Thr231Met) (rs80357001)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000049098 SCV000077111 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-10-29 criteria provided, single submitter clinical testing This sequence change replaces threonine with methionine at codon 231 of the BRCA1 protein (p.Thr231Met). The threonine residue is weakly conserved and there is a moderate physicochemical difference between threonine and methionine. This variant is present in population databases (rs80357001, ExAC 0.03%). This variant has been observed in individuals with a family history of breast and/or ovarian cancer (PMID: 21638052, 19949876). In one individual affected with breast cancer (Invitae), a pathogenic allele was also identified in BRCA1, which suggests that this c.692C>T variant was not the primary cause of disease in that individual. ClinVar contains an entry for this variant (Variation ID: 55669). Experimental studies have shown that this variant does not affect the expression of the full-length BRCA1 transcript, but increases expression of a naturally-occurring BRCA1 isoform that lacks exon 11 (PMID: 21638052). Another study has shown that this variant functionally complements BRCA1-deficient mouse embryonic stem cells (PMID: 23867111). 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.
GeneDx RCV000586691 SCV000210082 uncertain significance not provided 2018-08-24 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.692C>T at the cDNA level, p.Thr231Met (T231M) at the protein level, and results in the change of a Threonine to a Methionine (ACG>ATG). Using alternate nomenclature, this variant would be defined as BRCA1 811C>T. This variant has been observed in at least two individuals from high-risk breast and/or ovarian cancer families and was reported not to affect the expression level of full-length transcript, but was found to increase the level of a naturally occurring isoform in an RT-PCR based assay (van Harssel 2010, Brandao 2011). Additionally, Bouwman et al. (2013) concluded that BRCA1 Thr231Met is likely neutral based on an insensitivity to cisplatin and an ability to support cell growth similar to wild-type controls in a functional assay using BRCA1-deficient mouse embryonic stem cells. BRCA1 Thr231Met was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in a region known to interact with multiple proteins (Paul 2014). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether BRCA1 Thr231Met is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000162837 SCV000213324 uncertain significance Hereditary cancer-predisposing syndrome 2018-03-29 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Integrated Genetics/Laboratory Corporation of America RCV000586691 SCV000699293 uncertain significance not provided 2017-04-14 criteria provided, single submitter clinical testing Variant summary: The BRCA1 c.692C>T (p.Thr231Met) variant involves the alteration of a non-conserved nucleotide. 2/4 in silico tools predict a benign outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in 8/99174 control chromosomes at a frequency of 0.0000807, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA1 variant (0.0010005). The variant has been cited in HBOC patients without compelling evidence for pathogenicity (e.g. no co-segregation data provided). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. Two independent studies have shown that this variant has no impact on full length transcript but increases BRCA1delta11, the consequence of which is not known (Brandao_2011 and Tammaro_2014). Cisplatin (anticancer drug) sensitivity assay and growth proliferation of BRCA1 deficient ES cells support a benign outcome (Bouwman_2013). Taken together, because of the lack of clinical information and the unknown phenotypic consequence of increased BRCA1delta11 expression, the variant was classified as a variant of uncertain significance (VUS) until additional information becomes available.
Counsyl RCV000112772 SCV000785508 uncertain significance Breast-ovarian cancer, familial 1 2017-08-29 criteria provided, single submitter clinical testing
Color RCV000162837 SCV000910852 likely benign Hereditary cancer-predisposing syndrome 2017-01-22 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000586691 SCV001133643 likely benign not provided 2019-05-24 criteria provided, single submitter clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000112772 SCV000145665 uncertain significance Breast-ovarian cancer, familial 1 2002-06-20 no assertion criteria provided clinical testing

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