Submissions for variant NM_007294.4(BRCA1):c.212+1G>T

dbSNP: rs80358042

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000112019	SCV001161542	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2019-06-18	reviewed by expert panel	curation	IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 5 based on posterior probability = 0.998791
Labcorp Genetics (formerly Invitae), Labcorp	RCV000047717	SCV000075730	pathogenic	Hereditary breast ovarian cancer syndrome	2024-12-18	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 4 of the BRCA1 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or altered protein product. This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with clinical features of BRCA1-related conditions (PMID: 9333265, 11802209, 22516946, 22970155, 26848529). This variant is also known as IVS5+1G>T. ClinVar contains an entry for this variant (Variation ID: 54465). Studies have shown that disruption of this splice site results in activation of a cryptic splice site, and produces a non-functional protein and/or introduces a premature termination codon (PMID: 20215541, 22505045; internal data). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000218717	SCV000274249	pathogenic	Hereditary cancer-predisposing syndrome	2023-09-26	criteria provided, single submitter	clinical testing	The c.212+1G>T intronic pathogenic mutation results from a G to T substitution one nucleotide after coding exon 3 of the BRCA1 gene. This alteration has been identified in many, primarily Chinese, breast and/or ovarian and prostate cancer cohorts (Shattuck-Eidens et al. JAMA. 1997; 278:1243-1250; Choi MC et al. J Gynecol Oncol, 2018 Jul;29:e43; Li JY et al. Int. J. Cancer, 2019 01;144:281-289; Bhaskaran SP et al. Int. J. Cancer, 2019 Aug;145:962-973; Sun J et al. Clin. Cancer Res., 2017 Oct;23:6113-6119; Shi T et al. Int. J. Cancer, 2017 05;140:2051-2059; Leongamornlert D et al. Br. J. Cancer, 2012 May;106:1697-701). RNA experiments have shown that this alteration leads to the use of a cryptic splice donor site 22 nucleotides upstream of the native, leading to an out of frame transcript with a predicted alternate stop codon (Ambry internal data; Meindl et al. Int. J. Cancer. 2002; 97: 472–480). Close match substitutions at this position have shown the same splice defect (Ambry internal data; Houdayer C et al. Hum. Mutat., 2012 Aug;33:1228-38; Friedman LS et al. Am. J. Hum. Genet., 1995 Dec;57:1284-97; Menéndez M et al. Breast Cancer Res. Treat., 2012 Apr;132:979-92Sanz DJ et al. Clin. Cancer Res., 2010 Mar;16:1957-67). This nucleotide position is highly conserved in available vertebrate species. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. Based on the majority of available evidence to-date, this alteration is classified as a disease-causing mutation.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000112019	SCV000325241	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-10-02	criteria provided, single submitter	clinical testing
GeneDx	RCV000478644	SCV000564711	pathogenic	not provided	2017-04-06	criteria provided, single submitter	clinical testing	This variant is denoted BRCA1 c.212+1G>T or IVS4+1G>T and consists of a G>T nucleotide substitution at the +1 position of intron 4 of the BRCA1 gene. This variant is also known as BRCA1 331+1G>T or IVS5+1G>T using alternate nomenclature. The variant destroys a canonical splice donor site and has been shown to increase the usage of an upstream cryptic splice site and result in a truncated protein (Meindl 2002, Wappenschmidt 2012). This variant has been reported in high-risk breast and/or ovarian cancer families and in at least one prostate cancer case (Shattuck-Eidens 1997, Saxena 2002, Kwong 2012, Leongamornlert 2012). We consider this variant to be pathogenic.
GeneKor MSA	RCV000478644	SCV000693503	pathogenic	not provided	2020-01-01	criteria provided, single submitter	clinical testing	This variant occurs in the first base of intron 4 of the BRCA1 gene. This position is conserved in the human and other genomes and might be involved in mRNA processing. Therefore, this variant is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is also known as IVS5+1G>T in the literature. This variant has been reported in the literature in individuals and families with breast and/or ovarian cancer (PMID: 9333265, 11802209) as well as in an individual with prostate cancer (PMID: 22516946). The mutation database ClinVar contains entries for this variant (Variation ID: 54465).
Counsyl	RCV000112019	SCV000785886	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2017-12-28	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000218717	SCV000911510	pathogenic	Hereditary cancer-predisposing syndrome	2021-10-25	criteria provided, single submitter	clinical testing	This variant causes a G to T nucleotide substitution at the +1 position of intron 4 of the BRCA1 gene. RNA studies of this variant and two different SNV that disrupt c.212+1G found aberrant splicing resulting in the deletion of 22 nucleotides from the 3' end of the exon, which is predicted to cause frameshift and nonsense-mediated decay (PMID: 11802209, 23239986). This variant has intermediate impact on BRCA1 function in a haploid human cell proliferation assay (PMID: 30209399). This variant has been reported in individuals affected with breast and ovarian cancer (PMID: 9333265, 11802209, 12442273, 22970155, 28724667, 2975282, 29770616, 33471991; Eniu et al, 2017 poster, Annals of Oncology v43-v67. 10.1093/annonc/mdx362; Gomez-Flores-Ramos et al, 2020, doi: 10.20944/preprints202008.0718.v1; Color internal data) and an individual with prostate cancer (PMID: 22516946). 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.
All of Us Research Program, National Institutes of Health	RCV000112019	SCV004830326	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2024-01-05	criteria provided, single submitter	clinical testing	The c.212+1G>T variant of the BRCA1 gene is expected to affect mRNA splicing and result in an absent or disrupted protein product. This variant has been reported in multiple individuals with breast, ovarian and/or prostate cancer (PMID: 9333265, 11802209, 22516946, 22970155, 26848529, 28724667, 29752822, 29770616, 30702160). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Truncating variants in BRCA1 are known to be pathogenic (PMID: 21989022, 17661172, 22762150). Therefore, the c.212+1G>T variant of the BRCA1 gene is classified as pathogenic.
Breast Cancer Information Core (BIC) (BRCA1)	RCV000112019	SCV000144663	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	1999-06-21	no assertion criteria provided	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000112019	SCV000297588	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2012-06-04	no assertion criteria provided	clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000047717	SCV000587035	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353644	SCV000591252	pathogenic	Malignant tumor of breast		no assertion criteria provided	clinical testing	The c.212+1G>T variant was identified in 2 of 3574 proband chromosomes (frequency: 0.001) from individuals or families with hereditary breast and ovarian cancer (Meindl 2002, Shattuck-Eidens 1997). The variant was also identified in dbSNP (ID: rs80358042) “With pathogenic allele”, Clinvitae database (1X as pathogenic), LOVD, ARUP Laboratories BRCA Mutations Database (as definitely pathogenic), the ClinVar database (classified as a pathogenic variant) and the BIC database (5X with clinical importance). The c.212+1G>T variant is predicted to cause abnormal splicing because the nucleotide substitution occurs in the invariant region of the splice consensus sequence. In addition, 5 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic.
Brotman Baty Institute, University of Washington	RCV000112019	SCV001242564	not provided	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion provided	in vitro