BRCA1 NM_007294.3:c.301+7G>A, ?

Variant summary: BRCA1 c.301+7G>A alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. At least two publication reports experimental evidence evaluating an impact on splicing. These results showed no damaging effect of this variant (Steffensen_2014, Houdayer_2012). The variant allele was found at a frequency of 9.5e-05 in 251608 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in BRCA1 causing Hereditary Breast And Ovarian Cancer Syndrome (9.5e-05 vs 0.001), allowing no conclusion about variant significance. c.301+7G>A has been reported in the literature in individuals affected with Breast and Ovarian Cancer (Konstantopoulou_2008, Ratajska_2014, Kluska_2015). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. Six ClinVar submitters (evaluation after 2014) cite the variant as benign (4x) and likely benign (2x). Based on the evidence outlined above, the variant was classified as benign.

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Benign. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Fanconi anemia, complementation group S (MIM#617883), and susceptibility to breast and ovarian cancer (MIM#604370). (I) 0108 - This gene is associated with both recessive and dominant disease. Susceptibility to breast and ovarian cancer follows an autosomal dominant inheritance pattern, while Fanconi anemia is inherited in an autosomal recessive pattern (OMIM). (I) 0112 - The condition associated with this gene has incomplete penetrance. The highest estimate for cancer risk in carriers of pathogenic variants is 80% by the age of 70 years (PMID: 30551077). (I) 0210 - Splice site variant proven not to affect splicing of the transcript. (I) 0304 - Variant is present in gnomAD (v2) <0.001 (22 heterozygotes, 0 homozygotes). (SP) 0805 - This variant has strong previous evidence of being benign. This variant has been reported multiple times as benign or likely benign in the ClinVar database. It has been curated as benign by the Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) expert panel (PMID: 31131967). (SB) 1004 - This variant has moderate functional evidence supporting normal function. In vitro RNA studies have shown that this variant does not result in abnormal splicing (PMID: 22505045, 24667779). (SB) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

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