Submissions for variant NM_007294.4(BRCA1):c.5431C>T (p.Gln1811Ter)

dbSNP: rs397509283

Total submissions: 19

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000238731	SCV000323874	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2016-10-18	reviewed by expert panel	curation	Variant allele predicted to encode a truncated non-functional protein.
GeneDx	RCV000235642	SCV000293456	pathogenic	not provided	2023-11-13	criteria provided, single submitter	clinical testing	Nonsense variant predicted to result in protein truncation in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (gnomAD); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as 5550C>T; This variant is associated with the following publications: (PMID: 11773283, 22434525, 10644434, 24010542, 26300996, 25452441, 16944269, 29752822, 30209399, 29446198, 30825404, 31209999, 29297111, 29805665, 30352249, 31825140, 32438681, 34645131)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000238731	SCV000296394	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-10-10	criteria provided, single submitter	clinical testing
GeneKor MSA	RCV000235642	SCV000296782	pathogenic	not provided	2020-01-01	criteria provided, single submitter	clinical testing	This is a single base substitution, replacing the Glutamine at position 1811 of the BRCA1 protein by a Termination codon. It is expected to result in a truncated, non-functional protein. Truncating variants in BRCA1 are known to be pathogenic.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000238731	SCV000326311	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-10-02	criteria provided, single submitter	clinical testing
Counsyl	RCV000238731	SCV000785581	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2017-09-25	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000779877	SCV000916755	pathogenic	Hereditary breast ovarian cancer syndrome	2018-04-30	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.5431C>T (p.Gln1811X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (eg. c.5444G>A/p.Trp1815*, c.5470_5477delATTGGGCA). The variant was absent in 246268 control chromosomes (gnomAD). The variant, c.5431C>T, has been reported in the literature in multiple individuals affected with Hereditary Breast and Ovarian Cancer (Couch_2015, Fostira_2012, Siraj_2017). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Multiple ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as "pathogenic." Based on the evidence outlined above, the variant was classified as pathogenic.
Ambry Genetics	RCV001024097	SCV001186055	pathogenic	Hereditary cancer-predisposing syndrome	2022-11-02	criteria provided, single submitter	clinical testing	The p.Q1811* pathogenic mutation (also known as c.5431C>T), located in coding exon 21 of the BRCA1 gene, results from a C to T substitution at nucleotide position 5431. This changes the amino acid from a glutamine to a stop codon within coding exon 21. This mutation has been reported in multiple individuals with hereditary breast and/or ovarian cancer (Wagner T et al. Genomics, 1999 Dec;62:369-76; Findlay GM et al. Nature, 2018 10;562:217-222; Li JY et al. Int. J. Cancer, 2019 01;144:281-289; Rebbeck TR et al. Hum. Mutat., 2018 05;39:593-620; Wei H et al. Oncol Lett, 2018 Jun;15:9420-9428; Kotoula V et al. Am J Cancer Res, 2017 Jan;7:98-114; Alhuqail AJ et al. Breast Cancer Res. Treat., 2018 Apr;168:695-702; Laitman Y et al. Hum. Mutat., 2019 Jun). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Clinical Genetics and Genomics, Karolinska University Hospital	RCV000235642	SCV001450065	pathogenic	not provided	2019-12-19	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000779877	SCV001579205	pathogenic	Hereditary breast ovarian cancer syndrome	2024-12-12	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln1811*) in the BRCA1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 53 amino acid(s) of the BRCA1 protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with hereditary breast and/or ovarian cancer (PMID: 10644434, 22434525, 24010542, 25452441, 29446198, 29752822). This variant is also known as c.5550C>T. ClinVar contains an entry for this variant (Variation ID: 55577). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant disrupts a region of the BRCA1 protein in which other variant(s) (p.Arg1835*, p.Trp1815*) have been determined to be pathogenic (PMID: 8554067, 8968102, 11739404, 12360400, 20104584, 26187060, 27553291). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000235642	SCV002009420	pathogenic	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV000238731	SCV004027815	likely pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2023-05-08	criteria provided, single submitter	clinical testing	Criteria applied: PVS1_STR,PS4,PM2_SUP
Baylor Genetics	RCV000238731	SCV004216990	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2022-03-10	criteria provided, single submitter	clinical testing
Department of Human Genetics, Hannover Medical School	RCV004764759	SCV005374703	pathogenic	Pancreatic cancer, susceptibility to, 4	2024-10-11	criteria provided, single submitter	clinical testing	PVS1, PM2_Supporting, PM5_Strong
Institute of Human Genetics, University of Leipzig Medical Center	RCV004804023	SCV005423786	pathogenic	Familial cancer of breast	2024-11-19	criteria provided, single submitter	clinical testing	Criteria applied: PVS1,PM5_STR,PM2_SUP
Brotman Baty Institute, University of Washington	RCV000238731	SCV001238390	not provided	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion provided	in vitro
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000238731	SCV003927205	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2023-05-05	no assertion criteria provided	clinical testing	A pathogenic variant was detected in BRCA1 gene. This pathogenic mutation (also known as c.5494C>T), located in coding exon 23 of the BRCA1 gene, results from a C to T substitution at nucleotide position 5494. This changes the amino acid from a glutamine to a stop codon within coding exon 23 . This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. his mutation has been reported in multiple individuals with hereditary breast and/or ovarian cancer (PMID: 11773283, 22434525, 10644434, 24010542, 26300996, 25452441, 16944269, 29752822, 30209399, 29446198, 30825404, 31209999, 29297111, 29805665, 30352249, 31825140). Multiple ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as "pathogenic." Based on the evidence outlined above, the variant was classified as pathogenic. This variant was confirmed by Sanger sequencing .
Laboratory of Urology, Hospital Clinic de Barcelona	RCV003332111	SCV004040472	pathogenic	Malignant tumor of urinary bladder		no assertion criteria provided	research
BRCAlab, Lund University	RCV000238731	SCV004243915	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2020-03-02	no assertion criteria provided	clinical testing