ClinVar Miner

Submissions for variant NM_000059.4(BRCA2):c.2716A>G (p.Thr906Ala) (rs80358528)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV001719708 SCV000210581 likely benign not provided 2020-12-23 criteria provided, single submitter clinical testing
Ambry Genetics RCV000165093 SCV000215800 likely benign Hereditary cancer-predisposing syndrome 2018-10-04 criteria provided, single submitter clinical testing In silico models in agreement (benign)
Invitae RCV000204999 SCV000260479 likely benign Hereditary breast and ovarian cancer syndrome 2020-10-13 criteria provided, single submitter clinical testing
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000768588 SCV000324845 likely benign Breast and/or ovarian cancer 2015-09-20 criteria provided, single submitter clinical testing
Color Health, Inc RCV000165093 SCV000911027 benign Hereditary cancer-predisposing syndrome 2016-06-30 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000160218 SCV001737704 likely benign not specified 2021-05-27 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.2716A>G (p.Thr906Ala) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.8e-05 in 250434 control chromosomes (gnomAD and Guo_2020). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2716A>G has been reported in the literature as a non-informative genotype in at-least one patient with Ovarian adenocarcinoma (Aref-Eshghi_2020). This report however, does not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer Syndrome. At-least one co-occurrence with another pathogenic variant has been reported (BRCA1 c.3664G>T, p.Glu1222X), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five 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 benign (n=1) or likely benign (n=4). Based on the lack of evidence supporting an actionable outcome as outlined above, the variant was classified as likely benign to reflect the prevailing peer consensus.
Sharing Clinical Reports Project (SCRP) RCV000031379 SCV000053984 benign Breast-ovarian cancer, familial 2 2012-06-22 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000031379 SCV000146091 uncertain significance Breast-ovarian cancer, familial 2 2002-05-29 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000031379 SCV000591817 likely benign Breast-ovarian cancer, familial 2 no assertion criteria provided clinical testing The BRCA2 p.Thr906Ala variant was not identified in the literature, nor was it identified in the NHLBI Exome Sequencing Project (Exome Variant Server), HGMD, UMD, or LOVD databases. The variant was listed in dbSNP (ID: rs80358528) “With non-pathogenic allele”; however, no frequency information was provided, thus the prevalence of this variant in the general population could not be determined. The variant was identified in the BIC database 3X as a variant with unknown clinical importance, and was classified as a benign variant by the Sharing Clinical Reports Project (SCRP) (submitted within the ClinVar database and derived from Myriad reports). The p.Thr906 residue is not conserved across mammals and lower organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, MutationTaster) do not suggest a high likelihood of impact to the protein. However, this information is not predictive enough to rule out 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 predicted benign.

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