Submissions for variant NM_007294.4(BRCA1):c.5072C>T (p.Thr1691Ile)

dbSNP: rs80357034

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000048762	SCV000076775	pathogenic	Hereditary breast ovarian cancer syndrome	2023-10-04	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 1691 of the BRCA1 protein (p.Thr1691Ile). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast cancer, ovarian cancer, pancreatic cancer, and/or prostate cancer (PMID: 29202330, 29470806, 31843900; Invitae). It has also been observed to segregate with disease in related individuals. This variant is also known as c.5135C>T (p.Thr1712Ile). ClinVar contains an entry for this variant (Variation ID: 37628). An algorithm developed specifically for the BRCA1 gene suggests that this missense change is likely to be deleterious (PMID: 17305420). Experimental studies have shown that this missense change affects BRCA1 function (PMID: 20516115, 28781887, 30209399, 30257991, 30765603). Studies have shown that this missense change alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 25724305, 31843900). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000508659	SCV000568401	likely pathogenic	not provided	2024-08-06	criteria provided, single submitter	clinical testing	Exonic splice variant demonstrated to disrupt a natural splice donor site, leading to out-of-frame skipping of exon 16 (also known as exon 17 using alternate numbering), as well as a minor amount of normal transcript, as shown via mini-gene assay (PMID: 25724305); Variant classified as non-functional based on a saturation genome editing (SGE) assay measuring cell survival, that accounts for splice impact (PMID: 30209399); Published functional studies measuring protein impact demonstrate a damaging effect: severe folding defect, compromised phosphopeptide selectivity and transcriptional activation, and non-functional homology directed DNA repair (PMID: 20516115, 35665744, 32546644); In silico analysis supports a deleterious effect on splicing; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Identified in a patient with a personal history consistent with pathogenic variants in this gene (PMID: 29470806); Not observed in large population cohorts (gnomAD); Also known as 5191C>T; This variant is associated with the following publications: (PMID: 20516115, 17305420, 23867111, 25782689, 26913838, 28781887, 30209399, 30787465, 35665744, 31447099, 34597585, 30765603, 29470806, 31843900, 25348405, 32546644, 25724305)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000508659	SCV000605900	pathogenic	not provided	2023-11-29	criteria provided, single submitter	clinical testing	The BRCA1 c.5072C>T (p.Thr1691Ile) variant has been reported in the published literature in an individual affected with breast and/or ovarian cancer (PMID: 29470806 (2018)). Functional evidence suggests that this variant may impact protein function (PMIDs: 20516115 (2010), 23867111 (2013), 25724305 (2015), 30257991 (2018), 30209399 (2018), 30765603 (2019), and 31843900 (2019)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Analysis of this variant using software algorithms for the prediction of the effect of nucleotide changes on splicing yielded predictions that this variant may affect proper BRCA1 mRNA splicing. Based on the available information, this variant is classified as pathogenic.
Ambry Genetics	RCV000509720	SCV000608092	pathogenic	Hereditary cancer-predisposing syndrome	2021-12-22	criteria provided, single submitter	clinical testing	The p.T1691I pathogenic variant (also known as c.5072C>T), located in coding exon 15 of the BRCA1 gene, results from a C to T substitution at nucleotide position 5072. The threonine at codon 1691 is replaced by isoleucine, an amino acid with similar properties. Multiple RNA studies show that this alteration results in out-of-frame skipping of coding exon 15 (also called Exon 17 in the literature), however this event may be incomplete (Ambry internal data; Ahlborn LB et al. Breast Cancer Res. Treat. 2015 Apr; 150(2):289-98). One downstream functional study found that this nucleotide substitution is deleterious in a high throughput genome editing haploid cell survival assay and that this event may be, at least in part, due to an RNA defect (Findlay GM et al. Nature. 2018 10;562:217-222). In addition, multiple protein functional assays, including a cell-based transcription activation assay and a homology directed DNA repair assay found that this protein effect was non-functional leading to the possibility of a combined deleterious RNA and protein effect (Lee MS et al. Cancer Res. 2010 Jun; 70(12):4880-90; Petitalot A et al. Mol. Cancer Res. 2019 01;17:54-69). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Molecular Endocrinology Laboratory, Christian Medical College	RCV000031209	SCV002003991	likely pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1		criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000508659	SCV002022073	likely pathogenic	not provided	2019-01-28	criteria provided, single submitter	clinical testing
Mendelics	RCV002247402	SCV002518587	pathogenic	Familial cancer of breast	2022-05-04	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000031209	SCV000053809	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2007-03-06	flagged submission	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000031209	SCV000145286	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2004-02-20	flagged submission	clinical testing
Department of Medical Genetics, National Institute of Health	RCV000031209	SCV000787744	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2018-05-14	no assertion criteria provided	clinical testing	We identified the heterozygous variant NM_007294.3:c.5072C>T (p.Thr1691Ile) in BRCA1 gene in a Congolese family with four female cases of breast/ovarian cancer over two generations. This variant has previously been reported six times in families with hereditary breast and ovarian cancer syndrome. To date, there was a conflicting clinical significance of this variant in all databases from "Uncertain significance" in two reports to "likely pathogenic" in four others. This new report should contribute to improving the current pathogenicity ranking of this variant, c.5072C>T.
Brotman Baty Institute, University of Washington	RCV000031209	SCV001244016	not provided	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion provided	in vitro
King Laboratory, University of Washington	RCV001171419	SCV001251324	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1; Hereditary breast ovarian cancer syndrome	2019-09-01	no assertion criteria provided	research
PreventionGenetics, part of Exact Sciences	RCV004554633	SCV004742153	pathogenic	BRCA1-related disorder	2024-05-31	no assertion criteria provided	clinical testing	The BRCA1 c.5072C>T variant is predicted to result in the amino acid substitution p.Thr1691Ile. This variant has been reported in individuals with breast and/or ovarian cancer and in a cohort of individuals with breast, ovarian, endometrial, or colon cancer (Table S2, Singh et al. 2018. PubMed ID: 29470806; Tables S6 and S8, Casadei et al. 2019. PubMed ID: 31843900; Caputo et al. 2021. PubMed ID: 34597585). Real time-PCR and in vitro experimental studies suggest this variant impacts mRNA splicing and protein function (see, for example, Ahlborn et al. 2015. PubMed ID: 25724305; Casadei et al. 2019. PubMed ID: 31843900; Supplementary Figure 1a, Lee et al. 2010. PubMed ID: 20516115; Tables 1 and S2, Bouwman et al. 2020. PubMed ID: 32546644). Alternative nucleotide changes affecting the same amino acid (p.Thr1691Lys, p.Thr1691Arg) have been reported in ClinVar as likely pathogenic/pathogenic (see ClinVar IDs:37627, 55373). This variant has not been reported in a large population database, indicating it is rare. In Clinvar, this variant is reported as pathogenic or likely pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/37628/). This variant is interpreted as pathogenic.