ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.441A>G (p.Gln147=) (rs80358676)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) RCV000083105 SCV000578756 likely benign Breast-ovarian cancer, familial 2 2017-06-29 reviewed by expert panel curation Synonymous substitution variant, with low bioinformatic likelihood to result in a splicing aberration (Splicing prior probability 0.02;
Invitae RCV000044411 SCV000072424 likely benign Hereditary breast and ovarian cancer syndrome 2020-11-25 criteria provided, single submitter clinical testing
GeneDx RCV001719795 SCV000210239 likely benign not provided 2019-05-08 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 20492709, 21523855, 10923033, 30883759, 32123317)
Ambry Genetics RCV000163773 SCV000214354 likely benign Hereditary cancer-predisposing syndrome 2014-10-06 criteria provided, single submitter clinical testing This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Color Health, Inc RCV000163773 SCV000683620 likely benign Hereditary cancer-predisposing syndrome 2015-10-21 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000160020 SCV001363894 uncertain significance not specified 2019-05-22 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.441A>G alters a non-conserved nucleotide resulting in a synonymous change. Several computational tools predict a significant impact on normal splicing: Five predict the variant creates a 3 prime acceptor site. One publication reports experimental evidence that this variant affects mRNA splicing using a mini-gene assay (Fraile-Bethencourt_2019). However, this splicing effect has not been confirmed in patients. The variant allele was found at a frequency of 3.6e-05 in 250978 control chromosomes. To our knowledge, no occurrence of c.441A>G in individuals affected with Hereditary Breast and Ovarian Cancer has been reported. Co-occurrences with other pathogenic variant(s) have been reported (BRCA1 c.2389_2390delGA, p.Glu797Thrfs), providing supporting evidence for a benign role. Four 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 benign. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Sharing Clinical Reports Project (SCRP) RCV000083105 SCV000115179 benign Breast-ovarian cancer, familial 2 2012-05-01 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000083105 SCV000146868 uncertain significance Breast-ovarian cancer, familial 2 2004-02-20 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001354889 SCV001549608 likely benign Carcinoma of colon no assertion criteria provided clinical testing The BRCA2 p.Gln147= variant was not identified in the literature. The variant was identified in dbSNP (ID: rs80358676) as "With Likely benign, Uncertain significance allele”, ClinVar (classified as benign by Sharing Clinical Reports Project (SCRP); likely benign by Invitae, GeneDx, Ambry Genetics and two other submitters; as uncertain significance by BIC), LOVD 3.0 (1x as VUS), and in UMD-LSDB (3x as unclassified variant). The variant was identified in control databases in 8 of 245952 chromosomes at a frequency of 0.00003 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the European population in 8 of 111510 chromosomes (freq: 0.00007), while the variant was not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian, Finnish, and South Asian populations. The p.Gln147= variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. The variant occurs outside of the splicing consensus sequence and 4 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing. However, this information is not predictive enough to assume pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.

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