Submissions for variant NM_000059.4(BRCA2):c.5171T>C (p.Ile1724Thr)

dbSNP: rs80358743

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000044591	SCV000072604	likely benign	Hereditary breast ovarian cancer syndrome	2025-02-04	criteria provided, single submitter	clinical testing
GeneDx	RCV000985249	SCV000108619	likely benign	not provided	2020-12-14	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 24817641, 26295337, 30212499, 28301460, 29906251)
Ambry Genetics	RCV000131403	SCV000186379	likely benign	Hereditary cancer-predisposing syndrome	2018-01-17	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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000985249	SCV000296509	uncertain significance	not provided	2024-07-24	criteria provided, single submitter	clinical testing	The BRCA2 c.5171T>C (p.Ile1724Thr) variant has been reported in the published literature in individuals with lung cancer (PMID: 29906251 (2018)) and esophageal cancer (PMID: 31396961 (2020)). This variant has also been observed in a reportedly healthy individual (PMID: 33471991 (2021), see LOVD (http://databases.lovd.nl/shared/)), and described to be located in a region of the BRCA2 gene that is tolerant to missense sequence changes (PMID: 31911673 (2020)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.
Counsyl	RCV000113393	SCV000488145	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2016-02-19	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000131403	SCV000903516	likely benign	Hereditary cancer-predisposing syndrome	2018-06-13	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000074534	SCV000918852	uncertain significance	not specified	2024-02-06	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.5171T>C (p.Ile1724Thr) 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 was absent in 244828 control chromosomes (gnomAD and publication data). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.5171T>C has been reported in the literature in individuals affected with lung cancer and esophageal squamous cell carcinoma (e.g., Pietanza_2018, Ko_2019). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. Several publications have performed prediction analyses to classify the variant using several methods which incorporate data from probability of pathogenicity calculations and/or in silico tools, and have classified the variant as likely benign (e.g., Padilla_2019, Cline_2019, Parsons_2019). However, 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: 31294896, 24817641, 28301460, 31396961, 31112341, 31131967, 29906251). ClinVar contains an entry for this variant (Variation ID: 51803). Based on the evidence outlined above, the variant was classified as uncertain significance.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000131403	SCV003847051	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).
Breast Cancer Information Core (BIC) (BRCA2)	RCV000113393	SCV000146557	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	RCV001353973	SCV000591948	likely benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The p.Ile1724Thr variant has been previously reported in the BIC database with unknown clinical significance in three individuals; it has also been identified in one individual with a clinical history of breast/ovarian cancer by our laboratory. This residue is not conserved in mammals and computational analyses (SIFT, AlignGVGD) do not suggest a high likelihood of impact to the protein. However, this information is not predictive enough to rule out pathogenicity. This variant is listed in dbSNP with no frequency information (ID#:rs80358743). Another variant at the same amino acid position (c.5170A>G p.Ile1724Val) is listed as a polymorphism in dbSNP rs35335654 with an average heterozygosity of 0.027+/-0.112, increasing the likelihood the p.Ile1724Thr variant does not have clinical significance. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty although we would lean towards a more benign role for this variant. This variant is classified as Predicted Benign.