Our verdict is Likely benign. The variant received -6 ACMG points: 2P and 8B. PM2BP6_Very_Strong
The NM_007294.4(BRCA1):c.4992C>A(p.Leu1664Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. L1664L) has been classified as 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_benign. The variant received -6 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
BP6
Variant 17-43067690-G-T is Benign according to our data. Variant chr17-43067690-G-T is described in ClinVar as Likely_benign. ClinVar VariationId is 1192219.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Variant Effect in Transcripts
ACMG analysis was done for transcript: NM_007294.4. You can select a different transcript below to see updated ACMG assignments.
RefSeq Transcripts
Selected
Gene
Transcript
Tags
HGVSc
HGVSp
Effect
Exon Rank
Protein
UniProt
BRCA1
NM_007294.4
MANE Select
c.4992C>A
p.Leu1664Leu
synonymous
Exon 16 of 23
NP_009225.1
BRCA1
NM_001407581.1
c.5058C>A
p.Leu1686Leu
synonymous
Exon 17 of 24
NP_001394510.1
BRCA1
NM_001407582.1
c.5058C>A
p.Leu1686Leu
synonymous
Exon 17 of 24
NP_001394511.1
Ensembl Transcripts
Selected
Gene
Transcript
Tags
HGVSc
HGVSp
Effect
Exon Rank
Protein
UniProt
BRCA1
ENST00000357654.9
TSL:1 MANE Select
c.4992C>A
p.Leu1664Leu
synonymous
Exon 16 of 23
ENSP00000350283.3
BRCA1
ENST00000471181.7
TSL:1
c.5055C>A
p.Leu1685Leu
synonymous
Exon 17 of 24
ENSP00000418960.2
BRCA1
ENST00000470026.6
TSL:1
c.4992C>A
p.Leu1664Leu
synonymous
Exon 16 of 23
ENSP00000419274.2
Frequencies
GnomAD3 genomes
Cov.:
30
GnomAD4 exome
Cov.:
30
GnomAD4 genome
Cov.:
30
ClinVar
Significance: Likely benign
Submissions summary: Benign:2
Revision: criteria provided, multiple submitters, no conflicts
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing
Variant summary: BRCA1 c.4992C>A results in a synonymous change. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 251306 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, the variant, c.4992C>A, has not been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer Syndrome, and no experimental evidence demonstrating an impact on protein function has been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely benign.
Hereditary cancer-predisposing syndromeBenign:1
Oct 08, 2021
Ambry Genetics
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.