Submissions for variant NM_000059.4(BRCA2):c.9085G>A (p.Ala3029Thr)

gnomAD frequency: 0.00002  dbSNP: rs56179254

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001083149	SCV000073720	benign	Hereditary breast ovarian cancer syndrome	2024-01-31	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000129046	SCV000172960	benign	Hereditary cancer-predisposing syndrome	2014-08-07	criteria provided, single submitter	clinical testing	This alteration is classified as 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.
GeneDx	RCV000587355	SCV000210494	likely benign	not provided	2020-09-04	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 25682074, 18284688, 28678401, 28873162, 22228431, 20960228, 24884479, 19043619)
A.C.Camargo Cancer Center / LGBM, A.C.Camargo Cancer Center	RCV000413118	SCV000492499	uncertain significance	Breast neoplasm		criteria provided, single submitter	research
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000587355	SCV000695203	benign	not provided	2017-07-27	criteria provided, single submitter	clinical testing	Variant summary: The BRCA2 c.9085G>A (p.Ala3029Thr) variant involves the alteration of a conserved nucleotide and results in a replacement of a small size and hydrophobic Alanine (A) with a medium size and polar Threonine (T). 5/5 in silico tools predict a damaging outcome for this substitution. This variant was found in 6/117622 control chromosomes at a frequency of 0.000051, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA2 variant (0.0007503). This variant has been reported in multiple breast and/or ovarian patients; however, without strong evidence for causality. BIC has reported co-occurrence of this variant with pathogenic BRCA1 variants c.5263_5264insC and c.66_67delAG, one in each of the three samples and UMD also reported the variant to co-occur with a BRCA2 splice-site variant c.7436-2A>G, one internally tested individual had a co-occurrence with BRCA1 c.5266dupC. These co-occurrence data strongly suggest the variant to be benign. In support a benign outcome, a likelihood ratio in favor of protein loss of function was calculated to be neutral (Karchin_2008). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign/likely benign, including two laboratories have classified this variant as benign and likely benign, respectively, since last internal update. Taken together, this variant is classified as benign.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000587355	SCV000887957	likely benign	not provided	2022-11-04	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000129046	SCV000902679	likely benign	Hereditary cancer-predisposing syndrome	2015-09-09	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000129046	SCV002532002	likely benign	Hereditary cancer-predisposing syndrome	2021-10-02	criteria provided, single submitter	curation
Breast Cancer Information Core (BIC) (BRCA2)	RCV000114043	SCV000147531	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2002-05-29	no assertion criteria provided	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000114043	SCV000297574	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2008-10-02	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353636	SCV000592253	likely benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BRCA2 p.Ala3029Thr variant was identified in 5 of 5332 proband chromosomes (frequency: 0.0009) from individuals or families with head and neck squamous cell carcinoma orbreast or ovarian cancer (Lee 2008, Laitman 2011, Wong-Brown 2015, Silva 2014, Chandrasekharappa 2017). The variant was identified in dbSNP (rs56179254) as “with other allele”, ClinVar (classified as benign by Invitae, Ambry Genetics, Integrated Genetics and 2 other submitters; as likely benign by Color, GeneDx, and two other submitters; and as uncertain significance by BIC and A.C.Camargo Cancer Center), LOVD 3.0 (observed 1x) and UMD-LSDB (observed 3x). The variant was identified in control databases in 18 of 249,750 chromosomes at a frequency of 0.00007 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Ashkenazi Jewish in 17 of 10,048 chromosomes (freq: 0.002, increasing the likelihood this could be a low frequency benign variant ) and European in 1 of 112,594 chromosomes (freq: 0.000009), while itwas not observed in the African, Latino, East Asian, Finnish, Other or South Asian populations. The variant was reported in UMD-LSDB as co-occurring with a pathogenic BRCA2 variant (c.7436-2A>G) and in BIC as co-occurring with pathogenic BRCA1 variants (p.Gln1756Profs*74 and p.Glu23Valfs*17). The p.Ala3029Thr residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. 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.
BRCAlab, Lund University	RCV000114043	SCV004243850	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2020-03-02	no assertion criteria provided	clinical testing