Submissions for variant NM_007294.4(BRCA1):c.2612delinsTT (p.Pro871fs)

dbSNP: rs397508986

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000257105	SCV000323487	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.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000257105	SCV000325409	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-10-02	criteria provided, single submitter	clinical testing
GeneDx	RCV000478963	SCV000568418	pathogenic	not provided	2017-02-06	criteria provided, single submitter	clinical testing	This combined deletion and insertion is denoted BRCA1 c.2612delCinsTT at the cDNA level and p.Pro871LeufsX32 (P871LfsX32) at the protein level. Using alternate nomenclature, this variant would be defined as BRCA1 2731delCinsTT or c.2612delinsTT. The normal sequence, with the bases that are deleted and inserted in brackets, is GCTC[delC][insTT]GTTT. The variant causes a frameshift which changes a Proline to a Leucine at codon 871, and creates a premature stop codon at position 32 of the new reading frame. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. BRCA1 c.2612delCinsTT has been observed in a patient with triple negative breast cancer (Robertson 2012). We consider this variant to be pathogenic.
Ambry Genetics	RCV000572084	SCV000661061	pathogenic	Hereditary cancer-predisposing syndrome	2021-09-27	criteria provided, single submitter	clinical testing	The c.2612delCinsTT pathogenic mutation, located in coding exon 9 of the BRCA1 gene, results from the deletion of one nucleotide and insertion of two nucleotides causing a translational frameshift with a predicted alternate stop codon (p.P871Lfs*32). This alteration has been previously reported in an individual diagnosed with a triple negative breast cancer at the age of 28 and in a large, worldwide study of BRCA1/2 mutation positive families (Robertson L et al. Br. J. Cancer, 2012 Mar;106:1234-8; Rebbeck et al. Hum. Mutat. 2018 05;39(5):593-620). 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.
Invitae	RCV000697673	SCV000826298	pathogenic	Hereditary breast ovarian cancer syndrome	2019-06-08	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Pro871Leufs*32) in the BRCA1 gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals with a personal and/or family history of breast and/or ovarian cancer (PMID: 21702907, 22333603, 25685387). ClinVar contains an entry for this variant (Variation ID: 54620). Loss-of-function variants in BRCA1 are known to be pathogenic (PMID: 20104584). For these reasons, this variant has been classified as Pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000572084	SCV001359697	pathogenic	Hereditary cancer-predisposing syndrome	2019-11-20	criteria provided, single submitter	clinical testing	This variant deletes 1 nucleotide and inserts 2 nucleotides in exon 11 of the BRCA1 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in individuals affected with breast cancer (PMID: 31706072, 22333603). 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. Based on the available evidence, this variant is classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000697673	SCV002074496	pathogenic	Hereditary breast ovarian cancer syndrome	2022-01-31	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.2612delinsTT (p.Pro871LeufsX32) 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 282358 control chromosomes (gnomAD). c.2612delinsTT has been reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (e.g. Hondow_2011, Rebbeck_2018). These data indicate that the variant is very likely to be associated with disease. Six ClinVar submitters including an expert panel (ENIGMA) (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
BRCAlab, Lund University	RCV000257105	SCV004244082	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2020-03-02	no assertion criteria provided	clinical testing