Submissions for variant NM_000059.3(BRCA2):c.9493A>G (p.Thr3165Ala) (rs587782568)

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000131791	SCV000186840	likely benign	Hereditary cancer-predisposing syndrome	2018-04-10	criteria provided, single submitter	clinical testing	Co-occurence with a mutation in another gene that clearly explains a proband's phenotype;In silico models in agreement (benign)
Invitae	RCV001082356	SCV000283370	likely benign	Hereditary breast and ovarian cancer syndrome	2019-12-31	criteria provided, single submitter	clinical testing
GeneDx	RCV000657154	SCV000573397	uncertain significance	not provided	2018-06-27	criteria provided, single submitter	clinical testing	This variant is denoted BRCA2 c.9493A>G at the cDNA level, p.Thr3165Ala (T3165A) at the protein level, and results in the change of a Threonine to an Alanine (ACT>GCT). Using alternate nomenclature, this variant would be defined as BRCA2 9721A>G. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Thr3165Ala was not observed at a significant frequency in large population cohorts (Lek 2016). This variant is located within the DNA binding domain (Yang 2002). In silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether BRCA2 Thr3165Ala is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000657154	SCV000600863	uncertain significance	not provided	2020-04-10	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories	RCV000657154	SCV000885111	uncertain significance	not provided	2017-07-31	criteria provided, single submitter	clinical testing
Color Health, Inc	RCV000131791	SCV000911213	likely benign	Hereditary cancer-predisposing syndrome	2016-04-25	criteria provided, single submitter	clinical testing
Integrated Genetics/Laboratory Corporation of America	RCV000483383	SCV000916939	uncertain significance	not specified	2019-07-01	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.9493A>G (p.Thr3165Ala) results in a non-conservative amino acid change located in the OB3 fold (IPR015188) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 5.2e-05 in 251138 control chromosomes, predominantly at a frequency of 0.00038 within the Latino subpopulation in the gnomAD database. This frequency is not significantly higher than expected for a pathogenic variant in BRCA2 causing Hereditary Breast and Ovarian Cancer (5.2e-05 vs 0.00075), allowing no conclusion about variant significance. c.9493A>G has been reported in the literature in an individual with colorectal cancer (Ricker_2017) . This report does not provide an unequivocal conclusion about association of the variant with Hereditary Breast and Ovarian Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six ClinVar submissions (evaluation after 2014) cite the variant three times as likely benign and three times as uncertian significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Illumina Clinical Services Laboratory,Illumina	RCV001110138	SCV001267535	uncertain significance	Breast-ovarian cancer, familial 2	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Clinical Services Laboratory,Illumina	RCV001110139	SCV001267536	uncertain significance	Fanconi anemia, complementation group D1	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.