Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP6
The NM_007294.4(BRCA1):c.2690C>T(p.Pro897Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 1,613,750 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. P897S) 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]
Verdict is Uncertain_significance. Variant got 1 ACMG points.
PM2
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PM2 - Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium
Very rare variant in population databases, with high coverage;
BP6
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BP6 - Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 17-43092841-G-A is Benign according to our data. Variant chr17-43092841-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 156188.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=3, Likely_benign=2}.
Uncertain significance, criteria provided, single submitter
clinical testing
Ambry Genetics
Sep 22, 2023
The p.P897L variant (also known as c.2690C>T), located in coding exon 9 of the BRCA1 gene, results from a C to T substitution at nucleotide position 2690. The proline at codon 897 is replaced by leucine, an amino acid with similar properties. This alteration was detected in 1/86 hereditary breast and ovarian cancer families from Austria, and it was classified as a variant of unknown biological significance (Wagner TM et al. Int. J. Cancer, 1998 Jul;77:354-60). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Likely benign, criteria provided, single submitter
curation
University of Washington Department of Laboratory Medicine, University of Washington
Mar 23, 2023
Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673). -
Uncertain significance, criteria provided, single submitter
clinical testing
Color Diagnostics, LLC DBA Color Health
Apr 18, 2022
This missense variant replaces proline with leucine at codon 897 of the BRCA1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in a family affected with hereditary breast and ovarian cancer (PMID: 9663595). 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. -
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter
clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Dec 09, 2019
Variant summary: BRCA1 c.2690C>T (p.Pro897Leu) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 250908 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2690C>T has been reported in the literature in a family affected with Hereditary Breast and Ovarian Cancer (Wagner_1998). This report does not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. A ClinVar submitter (evaluation after 2014) cites the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -
Breast-ovarian cancer, familial, susceptibility to, 1 Benign:1
Likely benign, no assertion criteria provided
clinical testing
Sharing Clinical Reports Project (SCRP)
Nov 19, 2013
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Hereditary breast ovarian cancer syndrome Benign:1
Likely benign, criteria provided, single submitter