ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.612G>C (p.Leu204Phe) (rs80357394)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000225767 SCV000077083 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-12-21 criteria provided, single submitter clinical testing This sequence change replaces leucine with phenylalanine at codon 204 of the BRCA1 protein (p.Leu204Phe). The leucine residue is moderately conserved and there is a small physicochemical difference between leucine and phenylalanine. This variant is present in population databases (rs80357394, ExAC 0.02%). This variant has been reported in a study of individuals with breast cancer (PMID: 16267036) and in a screening of individuals at high risk for breast cancer (PMID: 9333265). This variant is also known as 731G>C in the literature. ClinVar contains an entry for this variant (Variation ID: 55646). 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 phenylalanine 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. 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 RCV000129590 SCV000184374 uncertain significance Hereditary cancer-predisposing syndrome 2017-09-22 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
GeneDx RCV000589445 SCV000210078 uncertain significance not provided 2018-09-28 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.612G>C at the cDNA level, p.Leu204Phe (L204F) at the protein level, and results in the change of a Leucine to a Phenylalanine (TTG>TTC). This variant, also denoted BRCA1 731G>C using alternate nomenclature, has been observed in at least one individual evaluated for hereditary breast and ovarian cancer (Judkins 2005). BRCA1 Leu204Phe was observed at an allele frequency of 0.01% (12/126,404) in individuals of European ancestry in large population cohorts (Lek 2016). This variant is located in the regions known to interact with BRD7 (Wang 1998, Harte 2010). 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 Leu204Phe is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000589445 SCV000699280 likely benign not provided 2016-07-22 criteria provided, single submitter clinical testing Variant summary: The BRCA1 c.612G>C (p.Leu204Phe) variant involves the alteration of a non-conserved nucleotide. 3/5 in silico tools predict a benign outcome. 4/5 splice prediction tools predict no significant impact on normal splicing. ESE finder predicts that this variant may not affect binding of ESE sites. The phenylalanine amino acid residue at codon 204 is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. In addition, the variant is not located in known functional domains of importance, such as the Ring finger, Serine-rich, or BCRT domains. One functional assay also shows that this variant does not affect normal splicing (Hudayer_2012). This variant was found in 10/113418 control chromosomes, predominantly observed in the European (Non-Finnish) subpopulation at a frequency of 0.0001609 (10/62134). This frequency is lower than the estimated maximal expected allele frequency of a pathogenic BRCA1 variant (0.0010005), however, it is still possible that the variant may be a rare benign polymorphism found in the populations of European (Non-Finnish) origin. UMD reports the variant in eight individuals with classification of "1-neutral" and it was found to co-occur with multiple deleterious BRCA2 variants, namely c.8904delC (p.Val2969CysfsX7), c.244A>T (p.Lys82X), and c.244A>T (p.Lys82X), strongly suggesting a benign outcome. Multiple clinical diagnostic laboratories classify this variant as uncertain significance however whether ExAC data and the co-occurrence data were used for evaluation of pathogenicity is unclear. The variant has also been reported in HBOC patients/families in literature, however, without co-segregation and co-occurrence information. Considering all, this variant has been classified as Likely Benign.
PreventionGenetics,PreventionGenetics RCV000589445 SCV000806980 uncertain significance not provided 2017-07-18 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000589445 SCV000888959 uncertain significance not provided 2018-05-29 criteria provided, single submitter clinical testing
Color RCV000129590 SCV000911052 likely benign Hereditary cancer-predisposing syndrome 2017-11-10 criteria provided, single submitter clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000112753 SCV000145642 uncertain significance Breast-ovarian cancer, familial 1 1999-03-24 no assertion criteria provided clinical testing

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