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

gnomAD frequency: 0.00002  dbSNP: rs80358528

Total submissions: 12

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	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.
Invitae	RCV000204999	SCV000260479	likely benign	Hereditary breast ovarian cancer syndrome	2024-01-31	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	2021-11-10	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	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.
Sema4, Sema4	RCV000165093	SCV002535518	likely benign	Hereditary cancer-predisposing syndrome	2021-12-20	criteria provided, single submitter	curation
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001719708	SCV004219552	uncertain significance	not provided	2023-05-03	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.000045 (5/112094 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In a large-scale breast cancer association study, the variant was observed in 8 individuals with breast cancer (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/BRCA2)). The variant has also been reported as somatic variant in an ovarian cancer tumor (PMID: 32483276 (2020)) as well as in an unaffected individual (PMID: 31837001 (2020)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.
PreventionGenetics, part of Exact Sciences	RCV003914880	SCV004729868	likely benign	BRCA2-related condition	2019-05-14	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Sharing Clinical Reports Project (SCRP)	RCV000031379	SCV000053984	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2012-06-22	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000031379	SCV000146091	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 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, susceptibility to, 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.