ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.5014_5016CAC[1] (p.His1673del) (rs80358343)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000048738 SCV000076751 likely pathogenic Hereditary breast and ovarian cancer syndrome 2018-09-04 criteria provided, single submitter clinical testing This sequence change deletes 3 nucleotides from exon 16 of the BRCA1 mRNA (c.5017_5019delCAC). This leads to the deletion of 1 amino acid residue in the BRCA1 protein (p.His1673del) but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (rs80358343, ExAC no frequency). This variant has been reported to segregate with breast and ovarian cancer in several families from the Italian region of Emilia-Romagna, and has also been found in individuals from other populations affected with breast and/or ovarian cancer (PMID: 11802209, 28186987, 27062684, 18092194, 19499246). This variant is also known as 5136delCAC in the literature. ClinVar contains an entry for this variant (Variation ID: 55355). Based on a multifactorial likelihood algorithm using genetic, in silico, and statistical data, this variant has been determined to have a high probability of being pathogenic (PMID: 28186987). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
GeneDx RCV000586937 SCV000570821 uncertain significance not provided 2017-10-17 criteria provided, single submitter clinical testing This in-frame deletion of 3 nucleotides in BRCA1 is denoted c.5017_5019delCAC at the cDNA level and p.His1673del (H1673del) at the protein level. The normal sequence, with the bases that are deleted in brackets, is ACAC[delCAC]ATCA. This deletion of a single Histidine residue occurs at a position that is not conserved and is located in the BRCT1 domain as well as a region known to interact with multiple other proteins (Paul 2014, UniProt). This variant has been observed in individuals with breast and/or ovarian cancer (Lim 2009, Ryu 2017, Zuntini 2017). Protein modeling suggests that this residue may play a role in protein stability (Coquelle 2011). Since in-frame deletions may or may not inhibit proper protein functioning, the clinical significance of this finding remains unclear at this time and we consider BRCA1 His1673del to be a variant of uncertain significance.
Color RCV000579949 SCV000683241 uncertain significance Hereditary cancer-predisposing syndrome 2018-01-30 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000586937 SCV000699193 uncertain significance not provided 2017-07-27 criteria provided, single submitter clinical testing Variant summary: The BRCA1 c.5017_5019delCAC (p.His1673del) variant involves the deletion of a string of three nucleotides resulting in an in-frame deletion of one amino acid. One in silico tool predicts a benign outcome for this variant. One functional study showed no effect on splicing for this variant (Houdayer_HM_2012). The variant of interest has not been found in 122066 control chromosomes. This variant has been reported in multiple individuals/families with breast and ovarian cancer, with some families showing incomplete co-segregation of variant with disease (Meindl_IJC_2002, Lim_BRCA1&2_J Cancer Res Clin Oncol_2009, Zuntini_Oncotarget_2017). One study identified the variant in 17 patients from 14 Italian families, with all probands sharing a common haplotype, suggesting that the deletion arose in a common ancestor living in this area (Zuntini_Oncotarget_2017). The overall calculated multi-likelihood ratio was 2,263,474:1 in favor of causality with higher prevalence of this variant in patients with the disease than in controls; authors also found loss of heterozygosity in 2/4 breast cancer and 6/6 ovarian cancer samples from patients with this variant. However, authors stated that the possibility of coexisting with another undetected pathogenic variant on the same ancestral allele cannot be excluded. Multiple clinical diagnostic laboratories/reputable databases and publications classified this variant as uncertain significance (before the publication of this study). Taken together, this variant is currently classified as possibly pathogenic until more definitive functional studies become available.
Mendelics RCV000112464 SCV001140496 likely pathogenic Breast-ovarian cancer, familial 1 2019-05-28 criteria provided, single submitter clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000112464 SCV000145262 uncertain significance Breast-ovarian cancer, familial 1 1999-04-05 no assertion criteria provided clinical testing

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