Submissions for variant NM_000059.4(BRCA2):c.2320A>G (p.Thr774Ala)

gnomAD frequency: 0.00006  dbSNP: rs55968715

Total submissions: 19

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000225743	SCV000071987	benign	Hereditary breast ovarian cancer syndrome	2024-01-31	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000131357	SCV000186333	benign	Hereditary cancer-predisposing syndrome	2014-11-19	criteria provided, single submitter	clinical testing	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, 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	RCV001719707	SCV000210576	likely benign	not provided	2019-08-06	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 24817641, 24728327, 24504028, 25348012, 27633797, 23555315)
Michigan Medical Genetics Laboratories, University of Michigan	RCV000031362	SCV000267752	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2016-04-21	criteria provided, single submitter	clinical testing
Counsyl	RCV000031362	SCV000488277	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2016-02-12	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000131357	SCV000902773	benign	Hereditary cancer-predisposing syndrome	2016-08-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000120313	SCV000919040	benign	not specified	2021-02-07	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.2320A>G (p.Thr774Ala) results in a non-conservative amino acid change in 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 4e-05 in 250976 control chromosomes, predominantly at a frequency of 7.1e-05 within the Non-Finnish European subpopulation in the gnomAD database. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2320A>G has been reported in the literature in individuals affected with Breast or Prostate cancer and Ovarian Cancer as well as in a patient with macrocytic thrombocytopenia (example, Haiman_2013, Cunningham_2014, Kager_2018). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. Multiple co-occurrences with other pathogenic variant(s) have been reported in public databases such as UMD and BIC as well as our laboratory (UMD-BRCA2 c.5576_5579delTTAA, p.Ile1859fsX3; BRCA1 c.3700_3704delGTAAA, p.Val1234GlnfsX8; BRCA1 c.4065_4068delTCAA, p.Asn1355LysfsX10; BIC-BRCA1 c.3255_3256insGA, p.Arg1085_Leu1086?fs; Our laboratory-BRCA1 c.2722G>T, p.Glu908X), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (likely benign/benign, n=6; VUS, n=1). Based on the evidence outlined above, the variant was classified as benign.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000120313	SCV001159027	likely benign	not specified	2018-07-02	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000131357	SCV002533308	likely benign	Hereditary cancer-predisposing syndrome	2021-08-18	criteria provided, single submitter	curation
University of Washington Department of Laboratory Medicine, University of Washington	RCV000131357	SCV003848222	likely benign	Hereditary cancer-predisposing syndrome	2023-03-23	criteria provided, single submitter	curation	Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673).
PreventionGenetics, part of Exact Sciences	RCV004532435	SCV004119125	uncertain significance	BRCA2-related disorder	2023-10-09	criteria provided, single submitter	clinical testing	The BRCA2 c.2320A>G variant is predicted to result in the amino acid substitution p.Thr774Ala. This variant has been reported in an individual with congenital macrocytic thrombocytopenia that also harbored a variant in another gene (Kager et al. 2018. PubMed ID: 29797310, Supplemental data, Patient 13), an individual with ovarian cancer (Cunningham et al. 2014. PubMed ID: 24504028, Table S1), and multiple individuals in the Breast Information Core (BIC) database (Szabo et al. 2000. PubMed ID: 10923033, https://research.nhgri.nih.gov/projects/bic; Breast Cancer Association Consortium et al. 2021. PubMed ID: 33471991). It has also been reported in a cohort of healthy adults (Bodian et al. 2014. PubMed ID: 24728327, Table S1, referred to as rs55968715; Breast Cancer Association Consortium et al. 2021. PubMed ID: 33471991). This variant is reported in 0.0071% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/13-32910812-A-G) and has conflicting interpretations of benign, likely benign, and uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/37781). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
CeGaT Center for Human Genetics Tuebingen	RCV001719707	SCV005041594	likely benign	not provided	2024-04-01	criteria provided, single submitter	clinical testing	BRCA2: BP4
Sharing Clinical Reports Project (SCRP)	RCV000031362	SCV000053967	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2009-11-19	no assertion criteria provided	clinical testing
ITMI	RCV000120313	SCV000084465	not provided	not specified	2013-09-19	no assertion provided	reference population
Breast Cancer Information Core (BIC) (BRCA2)	RCV000031362	SCV000146027	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	RCV000120313	SCV000591799	benign	not specified		no assertion criteria provided	clinical testing	The BRCA2 p.Thr774Ala variant was not identified in the literature. The variant was identified in dbSNP (ID: rs55968715), the ClinVar database (classified as a benign variant by Ambry Genetics and by the Sharing Clinical Reports Project (derived from Myriad reports)), the BIC database (6X with unknown clinical importance), and UMD (3X as an unclassified variant). In UMD the variant was identified in one sample with a co-occurring pathogenic BRCA2 variant (c.5576_5579delTTAA (p.Ile1859LysfsX3)) and in another sample with a co-occurring pathogenic BRCA1 variant (c.4065_4068delTCAA (p.Asn1355LysfsX10), increasing the likelihood that the p.Thr774Ala variant does not have clinical significance. The variant was identified by the Exome Variant Server project in 1 of 8600 European American alleles (frequency: 0.0001), although this low number of observations and low frequency is not substantive enough to determine the prevalence of the variant in the general population and its relationship to disease. The p.Thr774 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein. In addition, the variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. However, this information is not predictive enough to rule out pathogenicity. In summary, based on the above information, this variant meets our laboratory's criteria to be classified as benign.
True Health Diagnostics	RCV000131357	SCV000787923	likely benign	Hereditary cancer-predisposing syndrome	2017-07-12	no assertion criteria provided	clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000225743	SCV002050313	uncertain significance	Hereditary breast ovarian cancer syndrome	2021-11-09	no assertion criteria provided	clinical testing
Department of Medical and Surgical Sciences, University of Bologna	RCV000031362	SCV004228387	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2023-09-01	no assertion criteria provided	clinical testing	BS1(Supporting)+BP1(Strong)+BP5(Moderate) according to ACMG/AMP classification guidelines specified for BRCA1 & BRCA2 (Classification Criteria V1.0.0 2023-09-08 - https://cspec.genome.network/cspec/ui/svi/affiliation/50087) (PMID: 38160042)