ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.5014CAC[1] (p.His1673del) (rs80358343)

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Total submissions: 9
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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 2020-10-18 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 Health, Inc RCV000579949 SCV000683241 likely pathogenic Hereditary cancer-predisposing syndrome 2020-05-19 criteria provided, single submitter clinical testing This variant causes a deletion of histidine at codon 1673 in the BRCT1 domain of the BRCA1 protein. To our knowledge, functional studies have not been reported for this variant. In silico modeling has shown that His1673 in the BRCT domain of BRCA1 is predicted to interact with the BRCT domain of BARD1 (PMID 28186987). This variant has been reported in 17 individuals from 14 Italian families affected with breast or ovarian cancer (PMID: 28186987) and in multiple other unrelated individuals affected with breast and/or ovarian cancer (PMID: 11802209, 18092194, 19499246, 27062684, 30725392). A multifactorial likelihood analysis using genetic, in silico and tumor histopathology data has determined that this variant has a high probability of being pathogenic (PMID: 28186987). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Although additional studies are necessary to determine the mechanism of disease for this variant, this variant is classified as Likely Pathogenic based on the available clinical evidence.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp 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
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001002102 SCV001159949 uncertain significance not specified 2018-09-27 criteria provided, single submitter clinical testing The BRCA1 c.5017_5019delCAC; p.His1673del variant (rs80358343) has been described in the literature in multiple individuals with breast and ovarian cancer, with some families showing incomplete co-segregation of the variant with disease (Zuntini 2017). This variant is reported in the ClinVar database as both uncertain and likely pathogenic (Variation ID: 55355). It is absent from general population databases (1000 Genomes Project, Exome Variant Server, and Genome Aggregation Database), indicating it is not a common polymorphism. This variant deletes a single histidine residue leaving the rest of the predicted protein in-frame, but it is not known whether this deletion perturbs protein stability, structure etc.. This variant was predicted to be deleterious by the multifactorial ratio likelihood prediction model in fourteen families from the same region in Northern Italy; however, the lack of functional studies leaves the possibility that an alternate undetected variant is segregating with disease in these families that share an uncommon BRCA1 haplotype (Zuntini 2017). In summary, although the currently available evidence suggests that the variant is pathogenic, additional data are needed to prove that conclusively. Therefore, the clinical significance of the p.His1673del variant is uncertain at this time. REFERENCES Zuntini R et al. BRCA1 p.His1673del is a pathogenic mutation associated with a predominant ovarian cancer phenotype. Oncotarget. 2017 Apr 4;8(14):22640-22648.
Ambry Genetics RCV000579949 SCV001185296 likely pathogenic Hereditary cancer-predisposing syndrome 2019-04-24 criteria provided, single submitter clinical testing The c.5017_5019delCAC variant (also known as p.H1673del) is located in coding exon 15 of the BRCA1 gene. This variant results from an in-frame deletion of 3 nucleotides at positions 5136 to 5138. This results in the deletion of a histidine residue at codon 1673 that is not well conserved. This alteration has been reported in a German cohort of families with one or more cases of breast and at least one ovarian cancer (Meindl A et al, Int. J. Cancer 2002 Feb; 97(4):472-80). This alteration was also reported in 14 Northern Italian families with breast and/or ovarian cancer whose tumors demonstrated frequent BRCA1 loss-of-heterozygosity in tumors (Zuntini R et al. Oncotarget, 2017 Apr;8:22640-22648). This alteration segregates strongly with breast and ovarian cancer in multiple families (Ambry internal data; (Zuntini R et al. Oncotarget, 2017 Apr;8:22640-22648). This alteration is also designated as 5136 delCAC in the published literature. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000586937 SCV001470005 likely pathogenic not provided 2020-08-04 criteria provided, single submitter clinical testing Not found in the total gnomAD dataset, and the data is high quality. Found in at least one patient with expected phenotype for this gene. Located in potentially critical domain of the protein. Segregation with disease in unaffected individuals from multiple families.
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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