Submissions for variant NM_007294.4(BRCA1):c.3612del (p.Ala1206fs)

dbSNP: rs80357980

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000031114	SCV000299974	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	RCV000219713	SCV000276754	pathogenic	Hereditary cancer-predisposing syndrome	2022-11-10	criteria provided, single submitter	clinical testing	The c.3612delA pathogenic mutation, located in coding exon 9 of the BRCA1 gene, results from a deletion of one nucleotide at nucleotide position 3612, causing a translational frameshift with a predicted alternate stop codon (p.A1206Pfs*4). This mutation has been reported in multiple individuals/families with hereditary breast and ovarian cancer (HBOC) syndrome (Stoppa-Lyonnet D et al. Am. J. Hum. Genet. 1997 May;60:1021-30; Safra T et al. Ann. Oncol. 2013 Nov;24 Suppl 8:viii63-viii68; Meindl A et al. Int. J. Cancer. 2002 Feb;97:472-80). Of note, this alteration is also designated as 3731delA in published literature. 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.
GeneDx	RCV000255282	SCV000321430	pathogenic	not provided	2015-06-11	criteria provided, single submitter	clinical testing	This deletion of one nucleotide in BRCA1 is denoted c.3612delA at the cDNA level and p.Ala1206ProfsX4 (A1206PfsX4) at the protein level. The normal sequence, with the base that is deleted in braces, is GAAG[A]GGGG. The deletion causes a frameshift, which changes an Alanine to a Proline at codon 1206, and creates a premature stop codon at position 4 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.3612delA, previously reported as BRCA1 3731delA using alternate nomenclature, has been reported in association with breast and ovarian cancer (Stoppa-Lyonnet 1997, Safra 2013). we consider this variant to be pathogenic.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000031114	SCV000325700	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-10-02	criteria provided, single submitter	clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000255282	SCV001447581	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Invitae	RCV001386165	SCV001586299	pathogenic	Hereditary breast ovarian cancer syndrome	2023-05-22	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: 37533). This variant is also known as c.3731delA. This premature translational stop signal has been observed in individual(s) with breast and/or ovarian cancer (PMID: 9150149, 24131973). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Ala1206Profs*4) 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).
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000255282	SCV002046328	pathogenic	not provided	2020-10-21	criteria provided, single submitter	clinical testing	This frameshift variant has been reported in individuals suspected of having hereditary breast and/or ovarian cancer syndrome in the published literature (PMID: 24131973 (2002), 11802209 (2002), 9150149 (1997)). This variant has not been reported in large, multi-ethnic general populations. Based on the available information, this variant is classified as pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001386165	SCV002103840	pathogenic	Hereditary breast ovarian cancer syndrome	2022-02-28	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.3612delA (p.Ala1206ProfsX4) 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 251168 control chromosomes (gnomAD). c.3612delA has been reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (e.g. Rebbeck_2018, Safra_2013, Stoppa-Lyonnet_1997). 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. Seven ClinVar submitters, including one expert panel (ENIGMA) have assessed the variant since 2014: all have classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Sema4, Sema4	RCV000219713	SCV002538223	pathogenic	Hereditary cancer-predisposing syndrome	2021-12-21	criteria provided, single submitter	curation
Revvity Omics, Revvity	RCV000255282	SCV003826737	likely pathogenic	not provided	2021-12-16	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000031114	SCV004216893	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2022-10-26	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000219713	SCV004360224	pathogenic	Hereditary cancer-predisposing syndrome	2023-03-17	criteria provided, single submitter	clinical testing	This variant deletes 1 nucleotide in exon 10 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. This variant has been reported in individuals with breast and/or ovarian cancer (PMID: 9150149, 11802209, 24131973, 33471991). 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.
Sharing Clinical Reports Project (SCRP)	RCV000031114	SCV000053712	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2012-05-18	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000031114	SCV000144809	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2002-05-29	no assertion criteria provided	clinical testing
BRCAlab, Lund University	RCV000031114	SCV004244034	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2020-03-02	no assertion criteria provided	clinical testing