Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM1PM2
The NM_007294.4(BRCA1):c.5429T>G(p.Val1810Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. V1810E) 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: Uncertain_significance. The variant received 4 ACMG points.
PM1
In a hotspot region, there are 10 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 18 benign, 76 uncertain in NM_007294.4
PM2
Very rare variant in population databases, with high coverage;
Breast-ovarian cancer, familial, susceptibility to, 1Uncertain:2
Nov 14, 1997
Breast Cancer Information Core (BIC) (BRCA1)
Significance:Uncertain significance
Review Status:no assertion criteria provided
Collection Method:clinical testing
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May 28, 2019
Mendelics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing
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Malignant tumor of breastUncertain:1
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Department of Pathology and Laboratory Medicine, Sinai Health System
Significance:Uncertain significance
Review Status:no assertion criteria provided
Collection Method:clinical testing
The BRCA1 p.Val1810Gly variant was identified in 1 of 1978 proband chromosomes (frequency: 0.0005) from individuals or families with breast or ovarian cancer (Meindl 2002). The variant was identified in dbSNP (rs80357451) as “with uncertain significance allele”, ClinVar (classified as uncertain significance by BIC), LOVD 3.0 (observed 3x) and UMD-LSDB (observed 1x). The variant was not identified in the following control databases: the Exome Aggregation Consortium (August 8th 2016) or the Genome Aggregation Database (Feb 27, 2017). In vitro expression of the variant had a demonstrable effect on BRCA1 transactivation activity but did not alter protein stability and binding; these discordant results led the authors to classify this variant as having an uncertain effect on protein function (Lee 2010). The p.Val1810 residue is conserved across mammals and other organisms, and 5 of 5 computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -
Hereditary breast ovarian cancer syndromeUncertain:1
Apr 07, 2025
German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:curation
According to the ClinGen ENIGMA BRCA1 v1.1.0 criteria we chose these criteria: PM2 (supporting pathogenic): absent from gnomAD v4/3/2, BP4 (supporting benign): BayesDel no-AF = -0.2167 SpliceAI <=0.1; Based on evidence we decided that this criterion can not be selected: PS3 (strong pathogenic): Reported by three calibrated studies with discordant results. -