Submissions for variant NM_007294.4(BRCA1):c.670+16G>A

gnomAD frequency: 0.00005  dbSNP: rs199916228

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV001003384	SCV001161593	benign	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 1 based on posterior probability = 1.35E-06
Ambry Genetics	RCV000131335	SCV000186309	likely benign	Hereditary cancer-predisposing syndrome	2015-08-05	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
GeneDx	RCV000444606	SCV000512281	benign	not specified	2015-05-07	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001079367	SCV000560302	benign	Hereditary breast ovarian cancer syndrome	2024-01-09	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000131335	SCV000683342	likely benign	Hereditary cancer-predisposing syndrome	2017-01-17	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000587845	SCV000699285	likely benign	not provided	2017-02-13	criteria provided, single submitter	clinical testing	Variant summary: The BRCA1 c.670+16G>A variant involves the alteration of a non-conserved intronic nucleotide. One in silico tool predicts a benign outcome for this variant. This variant was found in 5/103692 control chromosomes at a frequency of 0.0000482, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA1 variant (0.0010005). However, this variant, which is found in 11 patients in the UMD database and 2 families in kConFab, is reported as co-occurring with a pathogenic variant in BRCA2 (c.7795_7797delGAA (p.Glu2599del)). Multiple clinical diagnostic laboratories/reputable databases classified this variant as "likely benign/polymorphysm". Similarly, 4/5 in silico tools (via Alamut) predict that this variant does not affect the normal splicing pattern and in functional studies the variant was shown to increase exon 10 inclusion (Steffensen_EJHG_2014). Taken together, this data strongly support non-pathogenicity, therefore the variant was classified as likely benign.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000444606	SCV004026809	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353415	SCV000591292	likely benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BRCA1 c.670+16G>A variant was identified in 1 of 2662 proband chromosomes (frequency: 0.0004) from individuals or families with breast and ovarian cancer (Hansen 2011). The variant was also identified in dbSNP (ID: rs199916228) as “With likely benign allele”, Clinvitae database (as likely benign by ClinVar), the ClinVar database (as likely benign by Ambry Genetics) and Fanconi Anemia Mutation Database (LOVD) (probably affects function). This variant was identified in the 1000 Genomes Project in 1 of 5000 chromosomes (frequency: 0.0002), NHLBI GO Exome Sequencing Project in 1 of 8600 European American alleles (freq. 0.0001) and Exome Aggregation Consortium database (March 14, 2016) in 5 of 103692 chromosomes (freq. 0.00005) in the following populations: European (Non-Finnish) in 4 of 56110 chromosomes (freq. 0.00007), South Asian in 1 of 14482 chromosomes (freq. 0.00007), although this low number of observations and low frequency is not substantive enough to determine the prevalence of the variant in the general population and its relationship to disease. The c.670+16G>A variant is located in the 5' splice region but does not affect the invariant +1 and +2 positions. However, positions +3 to +6 are part of the splicing consensus sequence and variants involving these positions sometimes affect splicing. In addition, 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing. The population study by Hansen (2011) identify the variant together with a disease-causing mutation, deletion of exon 18 and 19 in BRCA1, suggesting that this variant could be benign polymorphisms. However, the functional study by Steffensen (2014) observed the variant induced almost complete inclusion of exon 10 – an exon known to be involved in alternative splicing and therefore classified the variant as uncertain significance. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000587845	SCV001744364	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000587845	SCV001959656	likely benign	not provided		no assertion criteria provided	clinical testing