ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.107C>A (p.Ser36Tyr) (rs183557525)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000204917 SCV000259787 uncertain significance Hereditary breast and ovarian cancer syndrome 2015-12-20 criteria provided, single submitter clinical testing This sequence change replaces serine with tyrosine at codon 36 of the BRCA1 protein (p.Ser36Tyr). The serine residue is highly conserved and there is a large physicochemical difference between serine and tyrosine. This variant is present in population databases (rs183557525, <0.01%). This variant has been reported at a higher frequency in individuals from Cyprus with breast cancer (13/1174) compared to healthy controls (4/1109), however this observation has not been replicated to establish a clear association with breast cancer risk (PMID: 24695549). This variant has also been reported in an individual from a different population affected with hereditary breast and ovarian cancer (PMID: 21735045). Experimental studies have shown that this missense change may affect the sub-cellular localization of the BRCA1 protein, with an increased cytoplasmic retention compared to wild-type protein. It may also have reduced interaction with other proteins in the DNA repair pathway (PMID: 24695549). However, the clinical significance of these findings is unknown. In summary, this is a rare missense change that is observed in affected and unaffected individuals. Experimental evidence suggests this variant may impact some BRCA1 protein properties, but is insufficient to prove that it causes disease. Therefore, this change has been classified as a Variant of Uncertain Significance.
GeneDx RCV000587859 SCV000566735 uncertain significance not provided 2016-09-07 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.107C>A at the cDNA level, p.Ser36Tyr (S36Y) at the protein level, and results in the change of a Serine to a Tyrosine (TCC>TAC). This variant, also published as 226C>A using alternate nomenclature, was observed in individuals with male and female breast cancer of Cypriot ancestry (Christou 2014). While functional studies by Christou et al. (2014) demonstrated decreased, but not completely deficient, BRCA1 protein expression and BARD1 binding compared to wild-type, homology directed recombination assays by Lu et al. (2015) showed no difference from wild-type. BRCA1 Ser36Tyr was not observed at a significant allele frequency in the 1000 Genomes project. Since Serine and Tyrosine differ in some properties, this is considered a semi-conservative amino acid substitution. BRCA1 Ser36Tyr occurs at a position that is conserved in mammals and is located in the Ub site of the RING finger domain as well as a region known to interact with multiple other proteins (Wu 1996, Borg 2010, Paul 2014). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available information, it is unclear whether BRCA1 Ser36Tyr is a pathogenic variant or a benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000563749 SCV000661037 uncertain significance Hereditary cancer-predisposing syndrome 2017-12-19 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Conflicting evidence
Color RCV000563749 SCV000682934 uncertain significance Hereditary cancer-predisposing syndrome 2018-06-12 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000587859 SCV000698830 uncertain significance not provided 2016-10-06 criteria provided, single submitter clinical testing Variant summary: The BRCA1 c.107C>A (p.Ser36Tyr) variant located in the RING domain causing a missense change involving a conserved nucleotide with 5/5 in silico tools predicting a damaging outcome. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 1/113688, which does not exceed the estimated maximal expected allele frequency for a pathogenic BRCA1 variant of 1/1000. It has been reported in multiple affected individuals via publications, although limited information is provided (i.e. lack of co-occurrence and co-segregation data). Functional studies reported contradicting outcomes of the variant on the function of BRCA1. Multiple reputable clinical diagnostic laboratories and databases cite the variant with a classification of "uncertain significance." Therefore, the variant of interest of interest has been classified as a "Variant of Uncertain Significance (VUS)," until additional information becomes available.

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