ClinVar Miner

Submissions for variant NM_000059.4(BRCA2):c.7436-1G>T

dbSNP: rs886040939
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001193423 SCV001362227 likely pathogenic Hereditary breast ovarian cancer syndrome 2019-12-30 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.7436-1G>T is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes the canonical 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 251152 control chromosomes. c.7436-1G>T has been reported in the literature as a germline variant in at-least one individual of Japanese ancestry affected with Breast Cancer in a case control association study (Momozawa_2018). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp RCV001193423 SCV001581853 pathogenic Hereditary breast ovarian cancer syndrome 2020-10-27 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that disruption of this splice site alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 22505045, 31191615). This variant has been observed in individual(s) with breast cancer (PMID: 30287823). ClinVar contains an entry for this variant (Variation ID: 928867). This variant is not present in population databases (ExAC no frequency). This sequence change affects an acceptor splice site in intron 14 of the BRCA2 gene. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product.

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