Submissions for variant NM_000059.4(BRCA2):c.1631C>T (p.Thr544Ile)

gnomAD frequency: 0.00003  dbSNP: rs80358448

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001084269	SCV000071860	likely benign	Hereditary breast ovarian cancer syndrome	2023-12-05	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000130669	SCV000185555	likely benign	Hereditary cancer-predisposing syndrome	2018-05-23	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	RCV000586961	SCV000210565	likely benign	not provided	2020-12-15	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 22711857, 26580448, 25356972, 24817641, 25348012, 21952622)
Counsyl	RCV000083087	SCV000488320	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2016-02-25	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000212211	SCV000694550	likely benign	not specified	2024-02-29	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.1631C>T (p.Thr544Ile) 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 2e-05 in 251030 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. However, this variant has also been reported in 2/7325 European American women who were older than age 70, and cancer free (in the FLOSSIES database). c.1631C>T has been reported in the literature in sequencing studies with variable cohort characteristics, e.g. nonmucinous ovarian carcinoma (Alsop_2012), prostate cancer (Kote-Jarai_2011), positive family history of pancreatic cancer (Zhen_2015), exome and genome sequencing studies (Zhang_2015). In a large case-control study evaluating breast cancer (BrC) cases and controls in the Breast Cancer Association Consortium (BCAC) the variant was reported in 2/60466 cases and 1/53461 controls (Dorling_2021). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. Co-occurrences with other pathogenic variants have been reported (BRCA1 c.3756_3759delGTCT (p.Ser1253fs*10) in the UMD database; BRCA1 exon 12 dup in the BIC database; and a non-specified pathogenic variant in the BRCA1/2 gene, Alsop_2012), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 22711857, 34326862, 33471991, 24817641, 21952622, 31131967, 26580448, 25356972).ClinVar contains an entry for this variant (Variation ID: 51160). Based on the evidence outlined above, the variant was classified as likely benign.
Color Diagnostics, LLC DBA Color Health	RCV000130669	SCV000903012	benign	Hereditary cancer-predisposing syndrome	2015-11-16	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000586961	SCV001133685	likely benign	not provided	2019-07-09	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000586961	SCV002049959	uncertain significance	not provided	2021-07-09	criteria provided, single submitter	clinical testing	The BRCA2 c.1631C>T; p.Thr544Ile variant (rs80358448) is reported in the literature in an individual affected with acute lymphocytic leukemia, in an individual with prostate cancer and in an individual with family history of cancer, but the variant was not determined to be causative (Kote-Jarai 2011, Zhang 2015, Zhen 2015). This variant is also reported in an individual with ovarian cancer who also carried another pathogenic variant (Alsop 2012). The variant is reported with discrepant classifications in the ClinVar database (Variation ID: 51160) and is listed in the general population with an overall allele frequency of 0.002% (6/282,426 alleles) in the Genome Aggregation Database. The threonine at codon 544 is weakly conserved but computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.188). Due to limited information, the clinical significance of the p.Thr544Ile variant is uncertain at this time. References: Alsop K et al. BRCA mutation frequency and patterns of treatment response in BRCA mutation-positive women with ovarian cancer: a report from the Australian Ovarian Cancer Study Group. J Clin Oncol. 2012 Jul 20;30(21):2654-63. PMID: 22711857. Kote-Jarai Z et al. BRCA2 is a moderate penetrance gene contributing to young-onset prostate cancer: implications for genetic testing in prostate cancer patients. Br J Cancer. 2011 Oct 11;105(8):1230-4. PMID: 21952622. Zhang J et al. Germline Mutations in Predisposition Genes in Pediatric Cancer. N Engl J Med. 2015 Dec 10;373(24):2336-2346. PMID: 26580448. Zhen DB et al. BRCA1, BRCA2, PALB2, and CDKN2A mutations in familial pancreatic cancer: a PACGENE study. Genet Med. 2015 Jul;17(7):569-77. PMID: 25356972.
Sema4, Sema4	RCV000130669	SCV002533246	uncertain significance	Hereditary cancer-predisposing syndrome	2021-06-28	criteria provided, single submitter	curation
University of Washington Department of Laboratory Medicine, University of Washington	RCV000130669	SCV003851534	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).
Sharing Clinical Reports Project (SCRP)	RCV000083087	SCV000115161	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2012-05-01	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000083087	SCV000145901	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	1999-04-12	no assertion criteria provided	clinical testing