Submissions for variant NM_007294.4(BRCA1):c.3352C>T (p.Gln1118Ter)

dbSNP: rs397507215

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000031105	SCV000299929	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.
Ambry Genetics	RCV000167367	SCV000218219	pathogenic	Hereditary cancer-predisposing syndrome	2014-12-29	criteria provided, single submitter	clinical testing	The p.Q1118* pathogenic mutation (also known as c.3352C>T and 3471C>T), located in coding exon 9 of the BRCA1 gene, results from a C to T substitution at nucleotide position 3352. This changes the amino acid from a glutamine to a stop codon within coding exon 9. This alteration has been reported in one French HBOC family (Lecarpentier J, Breast Cancer Res. 2012 ; 14(4):R99). In addition to the clinical data presented in the literature, since premature stop codons are typically deleterious in nature, this alteration is interpreted as a disease-causing mutation (ACMG Recommendations for Standards for Interpretation and Reporting of Sequence Variations. Revision 2007. Genet Med. 2008;10:294).
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000031105	SCV000325628	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-10-02	criteria provided, single submitter	clinical testing
GeneDx	RCV000578536	SCV000680501	pathogenic	not provided	2017-10-03	criteria provided, single submitter	clinical testing	This pathogenic variant is denoted BRCA1 c.3352C>T at the cDNA level and p.Gln1118Ter (Q1118X) atthe protein level. Using alternate nomenclature, this variant would be defined as BRCA1 3471C>T. The substitutioncreates a nonsense variant, which changes a Glutamine to a premature stop codon (CAG>TAG), and is predicted tocause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. Thisvariant has been reported in families with breast and/or ovarian cancer (Lecarpentier 2012, Mannan 2016) and isconsidered pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001290608	SCV001478703	pathogenic	Hereditary breast ovarian cancer syndrome	2021-01-07	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.3352C>T (p.Gln1118X) 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. The variant was absent in 255376 control chromosomes (gnomAD and publication data). c.3352C>T has been reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (Rebbeck_2018, Singh_2018, Bhaskaran_2019). 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. Two ClinVar submitters and one expert panel (ENIGMA) (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae	RCV001290608	SCV002172964	pathogenic	Hereditary breast ovarian cancer syndrome	2022-11-10	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 37524). This premature translational stop signal has been observed in individual(s) with breast and/or ovarian cancer (PMID: 29446198, 30702160). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Gln1118*) 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).
Baylor Genetics	RCV000031105	SCV004217006	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2022-01-11	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000031105	SCV000053701	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2013-04-08	no assertion criteria provided	clinical testing
German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne	RCV000785370	SCV000923941	pathogenic	Neoplasm of ovary	2018-12-01	no assertion criteria provided	research