Submissions for variant NM_000059.4(BRCA2):c.10111A>G (p.Thr3371Ala)

gnomAD frequency: 0.00001  dbSNP: rs80358393

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000167810	SCV000071727	likely benign	Hereditary breast ovarian cancer syndrome	2024-02-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000131701	SCV000186738	likely benign	Hereditary cancer-predisposing syndrome	2018-08-23	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.
GeneDx	RCV000034424	SCV000210697	likely benign	not provided	2020-08-13	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 22703879, 27376475, 25682074, 20104584, 26580448, 26933808)
Counsyl	RCV000031301	SCV000221120	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2015-02-05	criteria provided, single submitter	literature only
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000043714	SCV000694494	likely benign	not specified	2023-09-07	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.10111A>G (p.Thr3371Ala) 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-06 in 251284 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.10111A>G has been reported in the literature in individuals affected with or undergoing testing for breast and/or other types of cancer (example, Borg_2010, Capanu_2011, Schenkel_2016, Wong-Brown_2015, Xiu_2016, Zhang_2015). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. Co-occurrences with other pathogenic variant have been reported (BRCA1 c.5335delC, p.Gln1779fsX14; BRCA1 c.4612C>T, p.Gln1538X; BRCA1 c.3778_3779insA, p.Leu1260fs), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Ten submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as likely benign.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000034424	SCV000883505	likely benign	not provided	2018-04-24	criteria provided, single submitter	clinical testing	The BRCA2 c.10111A>G; p.Thr3371Ala variant (rs80358393) has been described in individuals affected with breast cancer who also harbor a known pathogenic BRCA1 variant (see link to BIC database). This variant has also been observed in individuals with no personal or family history of cancer (Johnston 2012). It is reported in ClinVar (Variation ID: 37720) and observed in the general population at an overall frequency of 0.0007% (2/277018 alleles) in the Genome Aggregation Database. The threonine at codon 3371 is moderately conserved but computational algorithms (PolyPhen-2, SIFT) predict this variant to be tolerated. Based on available information, this variant is considered likely benign. References: BIC database: https://research.nhgri.nih.gov/bic/ Johnston J et al. Secondary variants in individuals undergoing exome sequencing: screening of 572 individuals identifies high-penetrance mutations in cancer-susceptibility genes. Am J Hum Genet. 2012 Jul 13;91(1):97-108.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000034424	SCV000888970	likely benign	not provided	2020-10-10	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000131701	SCV000902875	benign	Hereditary cancer-predisposing syndrome	2017-02-10	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000131701	SCV002533189	likely benign	Hereditary cancer-predisposing syndrome	2021-09-15	criteria provided, single submitter	curation
Fulgent Genetics, Fulgent Genetics	RCV002496479	SCV002808073	likely benign	Familial cancer of breast; Breast-ovarian cancer, familial, susceptibility to, 2; Fanconi anemia complementation group D1; Medulloblastoma; Wilms tumor 1; Malignant tumor of prostate; Pancreatic cancer, susceptibility to, 2; Glioma susceptibility 3	2021-12-11	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003964823	SCV004780061	likely benign	BRCA2-related condition	2020-02-24	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).
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000034424	SCV000043240	variant of unknown significance	not provided	2012-07-13	no assertion criteria provided	research	Converted during submission to Uncertain significance.
Sharing Clinical Reports Project (SCRP)	RCV000031301	SCV000053906	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2012-02-01	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000031301	SCV000145754	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2000-06-12	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353827	SCV000592312	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BRCA2 p.Thr3371Ala variant was identified in 3 of 4206 proband chromosomes (frequency: 0.001) from individuals or families with contralateral and unilateral breast cancer (Borg 2010). The variant was also previously identified by our laboratory in 1 individual with breast cancer. The p.Thr3371Ala variant was identified in the dbSNP with “Other” allele. This variant was identified in ClinVar database as likely benign by Ambry Genetics, GeneDX and Counsyl; as benign by Sharing Clinical Reports Project derived by Myriad Reports; as uncertain significance by Invitae, BIC and Biesecker laboratory ClinSeq Project NHGRI. The p.Thr3371Ala variant was identified in BIC 3x with unknown clinical importance; in BRCA Share UMD 1x and classified as unknown. The variant was not identified in NHLBI Exome Sequencing Project (Exome Variant Server), Exome Aggregation Consortium (released March 14, 2016), GeneInsight COGR, Clinvitae, COSMIC, MutDB, LOVD Fanconi’s Anemia Mutation and ARUP Laboratories Databases. Computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein. The p.Thr3371 residue is conserved in mammals and not in lower organism and the variant amino acid Alanine is present in chicken, increasing the likelihood that this variant does not have clinical significance. 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.
Genetic Services Laboratory, University of Chicago	RCV000043714	SCV003839273	likely benign	not specified	2022-04-28	no assertion criteria provided	clinical testing