Submissions for variant NM_007294.4(BRCA1):c.1066C>T (p.Gln356Ter)

dbSNP: rs80357215

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000111538	SCV000299530	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2016-09-08	reviewed by expert panel	curation	Variant allele predicted to encode a truncated non-functional protein.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000047325	SCV000075338	pathogenic	Hereditary breast ovarian cancer syndrome	2023-04-19	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln356*) in the BRCA1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BRCA1 are known to be pathogenic (PMID: 20104584). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with breast and ovarian cancer (PMID: 16683254, 30199306, 30606148). ClinVar contains an entry for this variant (Variation ID: 54114). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000162844	SCV000213331	pathogenic	Hereditary cancer-predisposing syndrome	2022-11-01	criteria provided, single submitter	clinical testing	The p.Q356* pathogenic mutation (also known as c.1066C>T), located in coding exon 9 of the BRCA1 gene, results from a C to T substitution at nucleotide position 1066. This changes the amino acid from a glutamine to a stop codon within coding exon 9. This mutation has been previously reported in several hereditary breast and ovarian cancer (HBOC) syndrome families (Tang NL et al. J. Natl. Cancer Inst. 1999 May;91:882-5; van der Hout AH et al. Hum. Mutat. 2006 Jul;27:654-66; Cotrim DP et al. BMC Cancer 2019 Jan;19:4; Siraj AK et al. Hum. Mutat. 2019 Mar; Abulkhair O et al. J Glob Oncol. 2018 Aug;4:1-9; Bhaskaran SP et al. Int. J. Cancer, 2019 Jan). This alteration was also identified in a large, worldwide study of BRCA1/2 mutation positive families (Rebbeck TR et al. Hum. Mutat. 2018 05;39:593-620). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical data presented in the literature, 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.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000111538	SCV000324943	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-10-02	criteria provided, single submitter	clinical testing
Genologica Medica	RCV000111538	SCV000577920	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2017-01-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000493346	SCV000582406	pathogenic	not provided	2015-09-18	criteria provided, single submitter	clinical testing	This pathogenic variant is denoted BRCA1 c.1066C>T at the cDNA level and p.Gln356Ter (Q356X) at the protein level. Using alternate nomenclature, this variant would also be defined as BRCA1 1185C>T. The substitution creates a nonsense variant, which changes a Glutamine to a premature stop codon (CAG>TAG), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant has been reported in at least four breast and/or ovarian cancer families (van der Hout 2006, Tang 1999) and is considered pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000162844	SCV001356327	pathogenic	Hereditary cancer-predisposing syndrome	2020-01-15	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 10 of the BRCA1 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of BRCA1 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000047325	SCV001362866	pathogenic	Hereditary breast ovarian cancer syndrome	2019-05-14	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.1066C>T (p.Gln356X) 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. The variant was absent in 251086 control chromosomes (gnomAD) but has been reported in the literature in multiple individuals affected with breast and ovarian cancer (e.g. Abulkhair _2018, Cotrim_2019, van der Hout_2006, Pajares_2018). 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. Six ClinVar submissions from clinical diagnostic laboratories and an expert panel (ENIGMA)(evaluation after 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics	RCV000111538	SCV004211730	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2021-10-28	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000047325	SCV004848652	pathogenic	Hereditary breast ovarian cancer syndrome	2022-11-03	criteria provided, single submitter	clinical testing	The p.Gln356X variant in BRCA1 has been reported in at least 8 individuals affected with breast and/or ovarian cancer (selected references: Abulkhair 2018 PMID: 30199306, Cotrim 2019 PMID: 30606148, van der Hout 2006 PMID: 16683254, Pajares 2018 PMID: 29884136, Siraj 2019 PMID: 30825404, Gao 2020 PMID: 31825140) and it was classified as pathogenic on Sep 08, 2016 by the ClinGen-approved Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) expert panel (Variation ID 54114). It was absent from large population studies. This nonsense variant leads to a premature termination codon at position 356, which is predicted to lead to a truncated or absent protein. Loss of function of the BRCA1 gene is an established disease mechanism in autosomal dominant hereditary breast and ovarian cancer syndrome. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant hereditary breast and ovarian cancer syndrome. ACMG/AMP Criteria applied: PVS1, PS4_Moderate, PM2_Supporting.
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre	RCV000111538	SCV005438352	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2024-12-18	criteria provided, single submitter	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000111538	SCV000143995	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2007-10-05	no assertion criteria provided	clinical testing
Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare	RCV000786906	SCV000925807	pathogenic	Familial cancer of breast	2018-11-16	no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000493346	SCV001740607	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000493346	SCV001906034	pathogenic	not provided		no assertion criteria provided	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000111538	SCV003927160	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2023-05-05	no assertion criteria provided	clinical testing	A pathogenic variant was detected in this sample . This variant changes 1 nucleotide in exon 10 of the BRCA1 gene, c.1066C>T (p.Gln356X) 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. his variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Also it has been reported in the literature in multiple individuals affected with breast and ovarian cancer (PMID: 30199306 , 30606148 , 29884136 ,16683254). 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. Twelve ClinVar submissions from clinical diagnostic laboratories and an expert panel (ENIGMA)(evaluation after 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. This variant confirmed by Sanger sequencing .
BRCAlab, Lund University	RCV000111538	SCV004244135	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2020-03-02	no assertion criteria provided	clinical testing