ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.3355A>T (p.Thr1119Ser) (rs80356949)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000048162 SCV000076175 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-04-10 criteria provided, single submitter clinical testing This sequence change replaces threonine with serine at codon 1119 of the BRCA1 protein (p.Thr1119Ser). The threonine residue is weakly conserved and there is a small physicochemical difference between threonine and serine. This variant is present in population databases (rs80356949, ExAC 0.001%). This variant has been observed in individuals  in the Breast Cancer Information Core database (PMID: 10923033). However, in one of those individuals a pathogenic allele was also identified in BRCA2, which suggests that this c.3355A>T variant was not the primary cause of disease. ClinVar contains an entry for this variant (Variation ID: 54855). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The serine 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 RCV000129260 SCV000184020 uncertain significance Hereditary cancer-predisposing syndrome 2018-04-23 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
GeneDx RCV000235634 SCV000292918 uncertain significance not provided 2015-12-04 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.3355A>T at the cDNA level, p.Thr1119Ser (T1119S) at the protein level, and results in the change of a Threonine to a Serine (ACT>TCT). Using alternate nomenclature, this variant would be defined as BRCA1 3474A>T. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA1 Thr1119Ser was not observed at a significant allele frequency in the NHLBI Exome Sequencing Project. Since Threonine and Serine share similar properties, this is considered a conservative amino acid substitution. BRCA1 Thr1119Ser occurs at a position that is not conserved and is not located in a known functional domain (Paul 2014). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available information, it is unclear whether BRCA1 Thr1119Ser is pathogenic or benign. We consider it to be a variant of uncertain significance.
Color RCV000129260 SCV000906799 likely benign Hereditary cancer-predisposing syndrome 2016-09-27 criteria provided, single submitter clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000112078 SCV000144735 uncertain significance Breast-ovarian cancer, familial 1 2003-12-23 no assertion criteria provided clinical testing

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