ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.1134C>A (p.Ser378Arg) (rs863224752)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000197019 SCV000254956 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-11-16 criteria provided, single submitter clinical testing This sequence change replaces serine with arginine at codon 378 of the BRCA1 protein (p.Ser378Arg). The serine residue is highly conserved and there is a moderate physicochemical difference between serine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with a BRCA1-related disease. ClinVar contains an entry for this variant (Variation ID: 216654). 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 disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, this variant has uncertain impact on BRCA1 function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics RCV000221820 SCV000277725 uncertain significance Hereditary cancer-predisposing syndrome 2015-08-13 criteria provided, single submitter clinical testing
GeneDx RCV000486943 SCV000567427 uncertain significance not provided 2017-08-17 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.1134C>A at the cDNA level, p.Ser378Arg (S378R) at the protein level, and results in the change of a Serine to an Arginine (AGC>AGA). Using alternate nomenclature, this variant would be defined as BRCA1 1253C>A. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA1 Ser378Arg was not observed in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Serine and Arginine differ in some properties, this is considered a semi-conservative amino acid substitution. BRCA1 Ser378Arg occurs at a position that is conserved across species and is located in a region known to interact with multiple proteins (Paul 2014). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether BRCA1 Ser378Arg is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Counsyl RCV000662726 SCV000785490 uncertain significance Breast-ovarian cancer, familial 1 2017-08-25 criteria provided, single submitter clinical testing
Color RCV000221820 SCV000909388 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-25 criteria provided, single submitter clinical testing

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