Submissions for variant NM_007294.4(BRCA1):c.4222C>T (p.Gln1408Ter)

gnomAD frequency: 0.00001  dbSNP: rs80356989

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)	RCV000077568	SCV000300094	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	RCV000214098	SCV000076505	pathogenic	Hereditary breast ovarian cancer syndrome	2023-10-23	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln1408*) 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 present in population databases (rs80356989, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with breast and/or ovarian cancer (PMID: 9333265, 9760198, 20104584, 22009639). This variant is also known as c.4341C>T. ClinVar contains an entry for this variant (Variation ID: 55145). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000131888	SCV000186943	pathogenic	Hereditary cancer-predisposing syndrome	2023-02-21	criteria provided, single submitter	clinical testing	The p.Q1408* pathogenic mutation (also known as c.4222C>T), located in coding exon 11 of the BRCA1 gene, results from a C to T substitution at nucleotide position 4222. This changes the amino acid from a glutamine to a stop codon within coding exon 11. This mutation was first reported in 1/798 individuals from a multi-center study of persons thought to be at elevated a priori risk for a BRCA1 mutation based on personal and/or family history (Shattuck-Eidens D et al. JAMA. 1997 Oct;278:1242-50). It was also detected in 3/989 unrelated individuals from a cohort of German breast and/or ovarian cancer families. These 3 individuals came from particularly high-risk families with two or more cases of breast cancer, including at least two cases with an age of onset under 50 years (Meindl A et al. Int. J. Cancer. 2002 Feb;97:472-80). The p.Q1408* pathogenic variant has also been reported in several Chinese patients with breast and/or ovarian cancer (Bhaskaran SP et al. Int. J. Cancer. 2019 08;145:962-973). Of note, this alteration is also designated as 4341C>T in some published literature. 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.
Eurofins Ntd Llc (ga)	RCV000236506	SCV000225649	pathogenic	not provided	2014-09-11	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000214098	SCV000271318	pathogenic	Hereditary breast ovarian cancer syndrome	2015-03-23	criteria provided, single submitter	clinical testing	The p.Gln1408X variant in BRCA1 has been previously reported in 2 women with bre ast and/or ovarian cancer and was found to segregate with disease in 6 affected members of 1 family with BRCA1-associated cancer, including 2 obligate carriers (Shattuck-Eidens 1997, Dong 1998). It has not been identified in large populatio n studies. This nonsense variant leads to a premature termination codon at posit ion 1408, which is predicted to lead to a truncated or absent protein. Heterozyg ous loss of BRCA1 function is an established disease mechanism in hereditary bre ast and ovarian cancer (HBOC). In summary, this variant meets our criteria to be classified as pathogenic for HBOC in an autosomal dominant manner based upon th e predicted impact to the protein, absence from controls, and segregation studie s.
GeneDx	RCV000236506	SCV000292518	pathogenic	not provided	2023-01-18	criteria provided, single submitter	clinical testing	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Observed in individuals with a personal or family history consistent with pathogenic variants in this gene (Shattuck-Eidens et al., 1997; Dong et al., 1998; Meindl et al., 2002; Borg et al., 2010); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Not observed at a significant frequency in large population cohorts (gnomAD); Also known as 4341C>T; This variant is associated with the following publications: (PMID: 9760198, 19340607, 29922827, 28888541, 9333265, 20104584, 22009639, 21993507, 26269718, 19941162, 11802209, 27433846, 21465171, 18824701, 16267036, 30702160, 29446198, 30720243, 25525159, 31825140, 32341426)
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000077568	SCV000325901	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-10-02	criteria provided, single submitter	clinical testing
Counsyl	RCV000077568	SCV000488183	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2016-01-19	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000131888	SCV000683164	pathogenic	Hereditary cancer-predisposing syndrome	2020-01-15	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 12 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 been identified in 1/251400 chromosomes 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	RCV000214098	SCV000699123	pathogenic	Hereditary breast ovarian cancer syndrome	2023-07-03	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.4222C>T (p.Gln1408X) 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 allele was found at a frequency of 4e-06 in 251400 control chromosomes. c.4222C>T has been reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome. 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. The following publications have been ascertained in the context of this evaluation (PMID: 16267036, 18824701, 11802209, 22009639, 19941162, 9333265, 21465171, 9760198, 27433846). 12 submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000236506	SCV000888911	pathogenic	not provided	2022-09-02	criteria provided, single submitter	clinical testing	This nonsense variant causes the premature termination of BRCA1 protein synthesis. The frequency of this variant in the general population, 0.0000088 (1/113696 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. In the published literature, the variant has been reported in individuals affected with breast cancer (PMID: 28724667 (2017), 32341426 (2020), 33302456 (2020)) and prostate cancer (PMID: 27433846 (2016), 29625052 (2018)). Based on the available information, this variant is classified as pathogenic.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000236506	SCV001446995	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000236506	SCV002550978	pathogenic	not provided	2024-07-31	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000077568	SCV004216945	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2023-11-02	criteria provided, single submitter	clinical testing
Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet	RCV000077568	SCV005045944	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2024-05-27	criteria provided, single submitter	clinical testing	PVS1; PM2_supporting; PM5_PTC_Strong
Sharing Clinical Reports Project (SCRP)	RCV000077568	SCV000109370	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2011-03-31	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000077568	SCV000145036	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2002-05-29	no assertion criteria provided	clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000214098	SCV000587383	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research
German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne	RCV000785414	SCV000923986	pathogenic	Ovarian neoplasm	2018-12-01	no assertion criteria provided	research