Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1PM2PM5PP3_Moderate
The NM_007294.4(BRCA1):c.203T>A(p.Ile68Lys) 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I68T) has been classified as Likely benign.
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 8 ACMG points.
PM1
In a hotspot region, there are 16 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 13 benign, 82 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 chr17-43106465-A-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 54445.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.859
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing
Variant summary: BRCA1 c.203T>A (p.Ile68Lys) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250482 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.203T>A has been reported in the literature as a VUS in individuals affected with breast cancer (example, Judkins_2005, Russo_2007, Gao_2020). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. Multiple publications report conflicting experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in a loss of Homology Directed Repair (HDR) activity (Findlay_2018) whereas earlier studies reported proficient HDR activity, proficient BARD binding, defective E3 ligase activity and UbcH5a binding (Morris_2006, Starita_2015). Furthermore, studies reporting BRCA1 tumor suppression being dependent on the ablation of phosphoprotein binding but not on its E3 ligase activity pose a challenge in using this as a measure of molecular pathogenesis in-vivo (Shakya_BRCA1_2011). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Breast-ovarian cancer, familial, susceptibility to, 1Uncertain:1
This missense variant replaces isoleucine with lysine at codon 68 of the BRCA1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. Functional studies had contradictory findings for this variant, reporting normal homology-directed DNA repair (PMID: 25823446) but loss-of-function in a haploid cell proliferation assay and ubiquitin E2 ligase binding and ligase activity in vitro (PMID: 30209399, 16403807). This variant has been analyzed by multifactorial analysis and classified as a variant of uncertain significance (PMID: 31131967). This variant has been reported in an individual affected with breast and/or ovarian cancer (PMID: 17221156). 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.
Hereditary breast ovarian cancer syndromeUncertain:1
Jan 10, 2023
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing
This sequence change replaces isoleucine, which is neutral and non-polar, with lysine, which is basic and polar, at codon 68 of the BRCA1 protein (p.Ile68Lys). 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: 17221156). ClinVar contains an entry for this variant (Variation ID: 54444). 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. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.