Submissions for variant NM_007294.4(BRCA1):c.2387C>T (p.Thr796Ile)

gnomAD frequency: 0.00005  dbSNP: rs80357364

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000047818	SCV000075831	likely benign	Hereditary breast ovarian cancer syndrome	2024-09-08	criteria provided, single submitter	clinical testing
GeneDx	RCV000588791	SCV000210130	uncertain significance	not provided	2014-08-15	criteria provided, single submitter	clinical testing	This variant is denoted BRCA1 c.2387C>T at the cDNA level, p.Thr796Ile (T796I) at the protein level, and results in the change of a Threonine to an Isoleucine (ACA>ATA). This variant, also known as 2506C>T using alternate nomenclature, has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA1 Thr796Ile was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Threonine and Isoleucine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA1 Thr796Ile occurs at a position that is moderately conserved across species and is not located in a known functional domain. In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether BRCA1 Thr796Ile is pathogenic or benign. We consider it to be a variant of uncertain significance.
Ambry Genetics	RCV000167276	SCV000218119	likely benign	Hereditary cancer-predisposing syndrome	2024-05-02	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.
Laboratory of Molecular Diagnosis of Cancer, West China Hospital, Sichuan University	RCV000240714	SCV000265884	uncertain significance	Breast neoplasm	2015-11-01	criteria provided, single submitter	research
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000588791	SCV000600285	likely benign	not provided	2023-08-31	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000167276	SCV000683030	uncertain significance	Hereditary cancer-predisposing syndrome	2022-10-17	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with isoleucine at codon 796 of the BRCA1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with breast cancer (PMID: 27257965, 28664449, 30093976, 30982232) and ovarian cancer (PMID: 27907908, 32068069). However, this variant has also been detected in a breast cancer case-control meta-analysis in 7/60463 cases and 6/53461 unaffected individuals with a calculated OR=1.032 (95%CI 0.347 to 3.07) and Fisher's Exact test p-value=1 (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA1_000198). This variant has been identified in 12/250512 chromosomes (12/18394 East Asian chromosomes) in the general population by the Genome Aggregation Database (gnomAD). The available evidence is not sufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001778691	SCV000698945	uncertain significance	not specified	2021-10-21	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.2387C>T (p.Thr796Ile) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.8e-05 in 250512 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in BRCA1 causing Hereditary Breast And Ovarian Cancer Syndrome (4.8e-05 vs 0.001), allowing no conclusion about variant significance. c.2387C>T has been reported in the literature in individuals affected with Breast or Ovarian Cancer (e.g. Chao_2016, Zhong_2016, Li_2017, Chan_2018, Wang_2019, Kwong_2020, Dorling_2021) but it was also reported in unaffected controls (Dong_2021, Dorling_2021). 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. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000167276	SCV003847712	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).
All of Us Research Program, National Institutes of Health	RCV004803972	SCV005428567	uncertain significance	BRCA1-related cancer predisposition	2024-07-23	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with isoleucine at codon 796 of the BRCA1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in individuals affected with breast cancer (PMID: 27257965, 28664449, 30093976, 30982232) and ovarian cancer (PMID: 27907908, 32068069). However, this variant has also been detected in a breast cancer case-control meta-analysis in 7/60463 cases and 6/53461 unaffected individuals with a calculated OR=1.032 (95%CI 0.347 to 3.07) and Fisher's Exact test p-value=1 (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA1_000198). This variant has been identified in 12/250512 chromosomes (12/18394 East Asian chromosomes) in the general population by the Genome Aggregation Database (gnomAD). Although there is a suspicion that this variant may not be associated with disease, additional studies are necessary to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance
Breast Cancer Information Core (BIC) (BRCA1)	RCV000111839	SCV000144399	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2002-05-29	no assertion criteria provided	clinical testing