ClinVar Miner

Submissions for variant NM_058216.3(RAD51C):c.404G>A (p.Cys135Tyr) (rs767796996)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000217463 SCV000278700 likely pathogenic Hereditary cancer-predisposing syndrome 2017-12-27 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Last nucleotide of exon,Deficient protein function in appropriate functional assay(s),In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Well-characterized mutation at same position
Color RCV000217463 SCV000909441 likely pathogenic Hereditary cancer-predisposing syndrome 2018-07-31 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000781793 SCV000920120 uncertain significance not specified 2018-05-25 criteria provided, single submitter clinical testing Variant summary: RAD51C c.404G>A (p.Cys135Tyr) results in a non-conservative amino acid change located in the DNA recombination and repair protein RecA-like, ATP-binding domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. Several computational tools predict a significant impact on normal splicing: Three predict the variant abolishes a 5 prime splicing donor site. One predict the variant weakens a 5 prime donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4.1e-06 in 241940 control chromosomes (gnomAD and publications). The variant, c.404G>A, has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer (Osorio_2012, Sanchez-Bermudez_2018). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in 30%-50% of normal activity. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Invitae RCV000458645 SCV000550186 likely pathogenic Fanconi anemia, complementation group O 2018-12-11 criteria provided, single submitter clinical testing This sequence change replaces cysteine with tyrosine at codon 135 of the RAD51C protein (p.Cys135Tyr). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and tyrosine. It also falls at the last nucleotide of exon 2 of the RAD51C coding sequence. This variant is present in population databases (rs767796996, ExAC 0.002%). This variant has been reported in an individual affected with breast and ovarian cancer (PMID: 22451500). It has also been observed in an individual with ovarian cancer (Invitae database). ClinVar contains an entry for this variant (Variation ID: 234175). Experimental studies have shown that this missense change results in a functionally impaired protein (PMID: 22451500). Nucleotide substitutions within the consensus splice site are relatively common causes of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of nucleotide changes on RNA splicing suggest that this variant may alter RNA splicing, but this prediction has not been confirmed by published transcriptional studies. Two additional variants affecting this nucleotide (c.404G>C, c.404G>T) have been shown to disrupt the naturally occurring RNA splicing of RAD51C, activating a cryptic donor splice site 27 nucleotides downstream in intron 2. The resultant reading frame contains a stop codon, that may trigger an NMD response. This suggests that this nucleotide is important for normal RNA splicing, and that other variants at this position may also be pathogenic. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Mendelics RCV000709503 SCV000839327 likely pathogenic Hereditary breast and ovarian cancer syndrome 2018-07-02 criteria provided, single submitter clinical testing

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