17-43045691-TG-TGG

Position:

• chr17-43045691-TG-TGG

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PVS1_Moderate PM2

The NM_007294.4(BRCA1):​c.5578dupC​(p.His1860fs) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,460,468 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: BRCA1 NM_007294.4 frameshift
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:7 B:1
• Conservation: PhyloP100: -0.167

Genes affected

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0025 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA1	NM_007294.4	c.5578dupC	p.His1860fs	frameshift_variant	23/23	ENST00000357654.9	NP_009225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9	c.5578dupC	p.His1860fs	frameshift_variant	23/23	1	NM_007294.4	ENSP00000350283.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1460468 Hom.: 0 Cov.: 32 AF XY: 0.00000551 AC XY: 4 AN XY: 726514

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000379

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.0000332

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:7 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:2 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jan 25, 2023	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. -
Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Dec 29, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jun 01, 2021	This variant inserts 1 nucleotide in exon 23 of the BRCA1 gene, creating a frameshift in the last coding exon. This variant is not expected to trigger nonsense-mediated decay and it causes a frameshift after the BRCT domain (PMID: 11573086, 20516115, 30765603). This variant has been reported in an individual affected with ovarian cancer (PMID: 30322717) and the clinical history of five carriers has been calculated to a likelihood ratio for pathogenicity of 0.090 (PMID: 31853058). 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. -

Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:1 Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Aug 24, 2023	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Jul 25, 2006	- -

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jan 08, 2025	Frameshift variant predicted to result in abnormal protein length as the last 4 amino acids are replaced with 19 different amino acids; Observed in an individual with epithelial ovarian cancer (PMID: 37718511); Logistical regression analysis used to predict carrier status based on personal and family history of cancer yielded 10:1 odds against pathogenicity (PMID: 31853058); Not observed at significant frequency in large population cohorts (gnomAD); Also known as 5697dup; This variant is associated with the following publications: (PMID: 24784157, 30322717, 10220405, 24389207, 10196224, 9738006, 9811458, 9926942, 9974970, 9159119, 11301010, 30765603, 37718511, 31853058, 31360874) -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Mar 13, 2024	The BRCA1 c.5578dup (p.His1860Profs*20) variant disrupts the translation stop codon of the BRCA1 mRNA and is predicted to cause BRCA1 protein elongation. This variant has been reported in the published literature in an individual with ovarian cancer (PMID: 30322717 (2018)) and in an undiagnosed individual (PMID: 24784157 (2014)). A study based on personal and family histories of five index cases with this variant reported that this variant had high odds against pathogenicity (PMID: 31853058 (2020)). Additionally, a functional study suggests that the variant is not damaging to protein function (PMID: 31853058 (2020)). The frequency of this variant in the general population, 0.000004 (1/247040 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Based on the available information, we are unable to determine the clinical significance of this variant. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Aug 10, 2022

Variant summary: BRCA1 c.5578dupC (p.His1860ProfsX20) causes a frameshift which results in an extension of the protein. This variant is located in the last exon and is unlikely to trigger nonsense mediated decay, but is predicted to replace the last 4 amino acids including the termination codon with 19 amino acids ending at a newly created stop signal, lengthening the C-terminus of the protein. The variant allele was found at a frequency of 4e-06 in 247040 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.5578dupC has been reported in the literature in an individual with Ovarian cancer undergoing multigene NGS panel testing (Carter_2018), as a reportable incidental variant in an individual tested by exome sequencing in the NIH Undiagnosed Diseases Program (Lawrence_2015), with a high odds against pathogenicity in 5 index cases tested by multigene panel testing (Li_2019), as a VUS in an individual with colorectal cancer (Toh_2018). These reports do 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 for this variant. A study performed in yeast suggests that amino acids from position 1855 of the protein to the C-terminal are dispensible for protein activation (Hayes_2000), however it is not clear how these findings would translate to human cells and additional functional studies are needed to substantiate these findings. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Some submitters cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Hereditary breast ovarian cancer syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 19, 2023

This sequence change results in a frameshift in the BRCA1 gene (p.His1860Profs*20). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 4 amino acid(s) of the BRCA1 protein and extend the protein by 15 additional amino acid residues. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This frameshift has been observed in individual(s) with colorectal cancer or ovarian tumor(s) (PMID: 30322717, 31360874). ClinVar contains an entry for this variant (Variation ID: 37683). 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. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs397507254; hg19: chr17-41197708;