ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.671-2A>G (rs80358108)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000258427 SCV000326386 pathogenic Breast-ovarian cancer, familial 1 2015-10-02 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000823108 SCV000699287 likely pathogenic Hereditary breast and ovarian cancer syndrome 2019-11-21 criteria provided, single submitter clinical testing Variant Summary: BRCA1 c.671-2A>G 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 a 3' acceptor site. Several publications report experimental evidence that this variant affects mRNA splicing with the most recent one confirming this observation utilizing RNA in situ hybridization to measure the absolute expression of BRCA1 mRNA splicing events in single lymphoblastoid cells containing this variant (Whiley_2014, Lattimore_2018, and Lattimore_2019). The variant was absent in 236750 control chromosomes. c.671-2A>G has been reported in at-least one individual the literature in a sequencing study of Australian women affected with Ovarian Cancer (Alsop_2012). This patient is also cited in the kConfab and Leiden Open Source variation databases and immortalized lymphoblastoid cell lines derived from this carrier were utilized in subsequent studies. In the absence of co-segregation studies, these report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. Two submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters classified the variant as pathogenic using overlapping evidences utilized in the context of this evaluation. Based on the evidence outlined above, until additional clinical cases of patients and families with this variant are reported, it was re-classified as likely pathogenic.
Invitae RCV000823108 SCV000963952 pathogenic Hereditary breast and ovarian cancer syndrome 2019-05-02 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 9 of the BRCA1 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed in a family undergoing testing for hereditary breast and/or ovarian cancer (PMID: 29446198). ClinVar contains an entry for this variant (Variation ID: 267617). Experimental studies have shown that this variant causes abnormal mRNA splicing (PMID: 24212087). Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in BRCA1 are known to be pathogenic (PMID: 20104584). For these reasons, this variant has been classified as Pathogenic.

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