ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.4048G>T (p.Gly1350Cys) (rs748674194)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000214306 SCV000275453 uncertain significance Hereditary cancer-predisposing syndrome 2015-05-11 criteria provided, single submitter clinical testing
Invitae RCV000231203 SCV000289791 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-11-12 criteria provided, single submitter clinical testing This sequence change replaces glycine with cysteine at codon 1350 of the BRCA1 protein (p.Gly1350Cys). The glycine residue is moderately conserved and there is a large physicochemical difference between glycine and cysteine. This variant is present in population databases (rs748674194, ExAC 0.01%). This variant has been observed in an individual with strong family cancer history (Invitae). However, in that individual a pathogenic allele was also identified in BRCA2 which suggests that this c.4048G>T variant was not the primary cause of disease. ClinVar contains an entry for this variant (Variation ID: 231563). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0". The cysteine 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.
GeneDx RCV000486044 SCV000571145 uncertain significance not provided 2017-04-20 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.4048G>T at the cDNA level, p.Gly1350Cys (G1350C) at the protein level, and results in the change of a Glycine to a Cysteine (GGC>TGC). Using alternate nomenclature, this variant would be defined as BRCA1 4167G>T. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA1 Gly1350Cys was not observed at a significant allele frequency in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Glycine and Cysteine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA1 Gly1350Cys occurs at a position that is not conserved and is located in the SCD domain as well as a region known to interact with multiple other proteins (Chen 1998, Narod 2004, Clark 2012). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether BRCA1 Gly1350Cys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.

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