Submissions for variant NM_000059.4(BRCA2):c.3910A>G (p.Thr1304Ala)

gnomAD frequency: 0.00003  dbSNP: rs28897723

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000044305	SCV000072318	likely benign	Hereditary breast ovarian cancer syndrome	2024-01-25	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000130607	SCV000185483	likely benign	Hereditary cancer-predisposing syndrome	2018-01-04	criteria provided, single submitter	clinical testing	This alteration is classified as likely 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	RCV000417556	SCV000515650	likely benign	not specified	2017-12-08	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Counsyl	RCV000031446	SCV000786159	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2018-03-12	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000130607	SCV000910964	benign	Hereditary cancer-predisposing syndrome	2016-02-22	criteria provided, single submitter	clinical testing
Mendelics	RCV000031446	SCV001139078	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2019-05-28	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001170462	SCV001333042	uncertain significance	Breast and/or ovarian cancer	2017-12-29	criteria provided, single submitter	clinical testing
University of Washington Department of Laboratory Medicine, University of Washington	RCV000130607	SCV003848525	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).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000417556	SCV004021079	uncertain significance	not specified	2023-06-20	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.3910A>G (p.Thr1304Ala) 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 3.4e-05 (i.e., 7 heterozygotes) in 208654 control chromosomes (gnomAD v2.1, Exomes dataset). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3910A>G has been reported in the literature in individuals affected with pancreatic cancer and cutaneous malignant melanoma (e.g., Goldstein_2017, Dudley_2018), however without strong evidence for causality in both cases. The variant has also been reported in a healthy control (e.g., Momozawa_2018) as well as in 2 carriers in a healthy cohort of women over the age of 70 who have never had cancer (FLOSSIES database). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight submitters have reported clinical-significance assessments for this variant to ClinVar after 2014 with conflicting assessments (VUS, n = 2; Likely benign, n = 5; Benign, n = 1). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000417556	SCV004024411	uncertain significance	not specified	2023-08-15	criteria provided, single submitter	clinical testing
MGZ Medical Genetics Center	RCV003607206	SCV004543891	likely benign	Familial cancer of breast	2024-02-09	criteria provided, single submitter	clinical testing	ACMG codes applied following ENIGMA VCEP rules: BS1_SUP, BP1_STR
Sharing Clinical Reports Project (SCRP)	RCV000031446	SCV000054051	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2009-02-02	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000031446	SCV000146330	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	RCV001353744	SCV000591881	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BRCA2 p.Thr1304Ala variant was not identified in the literature in a patient population. The variant was identified in dbSNP (ID: rs28897723 as "With other allele"), ClinVar (1x as benign by SCRP; 3x as likely benign by Ambry Genetics, GeneDx, and Invitae; and 4x as uncertain significance by Counsyl, BI, CHEO Genetics Diagnostic Laboratory, and at Sinai Health System), MutDB, LOVD 3.0 (2x), and UMD-LSDB (8x as unclassified variant). The variant was not identified in Cosmic, ARUP Laboratories, or Zhejiang University databases. The variant was identified in control databases in 7 of 205258 chromosomes at a frequency of 0.00003 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Other in 1 of 4492 chromosomes (freq: 0.0002) and European in 6 of 95212 chromosomes (freq: 0.00006); it was not observed in the African, Latino, Ashkenazi Jewish, East Asian, Finnish, or South Asian populations. The p.Thr1304 residue is not conserved in mammals and 5 of 5 computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 5 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) 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. This variant is classified as a variant of uncertain significance.
PreventionGenetics, part of Exact Sciences	RCV004532440	SCV004711881	likely benign	BRCA2-related disorder	2023-06-15	no assertion criteria provided	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).