Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM1PM2PM5PP3_ModeratePP5
The NM_007294.4(BRCA1):c.5258G>C(p.Arg1753Thr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1753K) has been classified as Uncertain significance.
BRCA1 (HGNC:1100): (BRCA1 DNA repair associated) This gene encodes a 190 kD nuclear phosphoprotein that plays a role in maintaining genomic stability, and it also acts as a tumor suppressor. The BRCA1 gene contains 22 exons spanning about 110 kb of DNA. The encoded protein combines with other tumor suppressors, DNA damage sensors, and signal transducers to form a large multi-subunit protein complex known as the BRCA1-associated genome surveillance complex (BASC). This gene product associates with RNA polymerase II, and through the C-terminal domain, also interacts with histone deacetylase complexes. This protein thus plays a role in transcription, DNA repair of double-stranded breaks, and recombination. Mutations in this gene are responsible for approximately 40% of inherited breast cancers and more than 80% of inherited breast and ovarian cancers. Alternative splicing plays a role in modulating the subcellular localization and physiological function of this gene. Many alternatively spliced transcript variants, some of which are disease-associated mutations, have been described for this gene, but the full-length natures of only some of these variants has been described. A related pseudogene, which is also located on chromosome 17, has been identified. [provided by RefSeq, May 2020]
BRCA1 Gene-Disease associations (from GenCC):
breast-ovarian cancer, familial, susceptibility to, 1
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
Our verdict: Likely_pathogenic. The variant received 9 ACMG points.
PM1
In a hotspot region, there are 15 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 15 benign, 80 uncertain in NM_007294.4
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr17-43057072-T-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 801086.Status of the report is reviewed_by_expert_panel, 3 stars.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.9
PP5
Variant 17-43057071-C-G is Pathogenic according to our data. Variant chr17-43057071-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 55488.
Quest Diagnostics Nichols Institute San Juan Capistrano
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing
A missense variant with dominant inheritance. Variant has been observed in multiple individuals with hereditary breast and ovarian cancer and one instance of male breast cancer (PMID 25066507, 19016756, internal patients), while not found in a large general population study (gnomAD dataset, and the data is high quality (0/277244 chr)). Located in a potentially critical domain of the protein. Damaging to protein function(s) relevant to disease mechanism (PMID: 30209399, 28781887, 23867111, 21447777, 20516115, 17308087). ClinVar contains an entry for this variant: 55488. -
Hereditary breast ovarian cancer syndromePathogenic:1
Apr 10, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Likely pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing
This sequence change replaces arginine, which is basic and polar, with threonine, which is neutral and polar, at codon 1753 of the BRCA1 protein (p.Arg1753Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast and/or ovarian cancer (PMID: 19016756, 25066507). ClinVar contains an entry for this variant (Variation ID: 55488). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 30209399) indicates that this missense variant is expected to disrupt BRCA1 function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects BRCA1 function (PMID: 17308087, 20516115, 23867111, 30209399). 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. -
Breast carcinomaPathogenic:1
Aug 09, 2021
Medical Genetics Laboratory, Umraniye Training and Research Hospital, University of Health Sciences
This missense variant replaces arginine with threonine at codon 1753 of the BRCA1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function. Functional studies have reported conflicting findings for this variant protein. Functional studies have reported that this variant impacted BRCA1 function in transcription activation and phosphopeptide binding assays, a haploid cell proliferation assay and BRCA1 peptide stability (PMID: 17308087, 20516115, 30209399). Studies using mouse Brca1-deficient embryonic stem cells have reported conflicting loss-of-function and no impact in homology-directed DNA repair assays and no impact on cisplatin and PARP inhibitor sensitivity assays (PMID: 23867111, 32546644). This variant has been reported in at least two individuals affected with ovarian cancer or both ovarian and breast cancer (PMID: 19016756, 25066507, 32059136) and two individuals affected with breast cancer (PMID: 25066507) and in a suspected hereditary breast and ovarian cancer family (DOI: 10.1515/tjb-2019-0424). A multifactorial analysis also has reported likelihood ratios for pathogenicity based on co-occurrence with a pathogenic variant and family history of 1.0673 and 4.0078, respectively (PMID: 31131967). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
Familial cancer of breastOther:1
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ClinVar Staff, National Center for Biotechnology Information (NCBI)