rs876659614

chr17-43099880-G-Achr17-43099880-G-Cchr17-43099880-G-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP3 PP5

The NM_007294.4(BRCA1):c.442C>T(p.Gln148Ter) variant causes a stop gained, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 31)
• Consequence: BRCA1 NM_007294.4 stop_gained, splice_region
• Scores: Splicing: ADA: 0.9871
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4 U:3
• Conservation: PhyloP100: 4.20

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]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
• PP5: Variant 17-43099880-G-A is Pathogenic according to our data. Variant chr17-43099880-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 232203.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=3, Likely_pathogenic=2, Pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA1	NM_007294.4	c.442C>T	p.Gln148Ter	stop_gained, splice_region_variant	7/23	ENST00000357654.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA1	ENST00000357654.9	c.442C>T	p.Gln148Ter	stop_gained, splice_region_variant	7/23	1	NM_007294.4	P4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 31

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4 Uncertain:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 29, 2021	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Has not been previously published as pathogenic or benign to our knowledge; Not observed in large population cohorts (Lek 2016); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as 561C>T; This variant is associated with the following publications: (PMID: 31131967) -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Mar 14, 2023	- -

Hereditary breast ovarian cancer syndrome Pathogenic:1 Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 19, 2018	Variant summary: BRCA1 c.442C>T (p.Gln148X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (eg. c.470_471delCT, p.Ser157X; c.485_486delTG, p.Val162fsX19; c.552dupT, p.Asp185X). The variant was absent in 121408 control chromosomes (ExAC). To our knowledge, no occurrence of c.442C>T in individuals affected with Hereditary Breast and Ovarian Cancer and no experimental evidence demonstrating its impact on protein function have been reported. One clinical diagnostic laboratory classified the variant as pathogenic in ClinVar after 2014 without evidence for independent evaluation. Based on the evidence outlined above, the variant was classified as likely pathogenic. -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Aug 28, 2023	This sequence change creates a premature translational stop signal (p.Gln148*) in the BRCA1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BRCA1 are known to be pathogenic (PMID: 20104584). However, RNA analysis indicates that alternative usage of a cryptic splice site in exon 7, which results in the in-frame skipping of Gln148 amino acid residue, may functionally rescue this variant. 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. RNA studies show that the effect of this premature translational stop signal can be potentially rescued by a naturally-occurring isoform that results in skipping of the last amino acid residue of exon 7 (also known as exon 8), but is expected to preserve the integrity of the reading-frame (PMID: 28905878, 24569164, Invitae). ClinVar contains an entry for this variant (Variation ID: 232203). This premature translational stop signal has been observed in individual(s) with ovarian cancer (PMID: 28888541). This variant is not present in population databases (gnomAD no frequency). -

Hereditary cancer-predisposing syndrome Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	May 26, 2021	The p.Q148* variant (also known as c.442C>T), located in coding exon 6 of the BRCA1 gene, results from a C to T substitution at nucleotide position 442. This changes the amino acid from a glutamine to a stop codon within coding exon 6. RNA studies have shown that there is significant use of an alternative splice acceptor site at the beginning of coding exon 6 that would remove this alteration from the final transcript and result in a potentially functional protein (Ambry internal data; Colombo M et al. Hum Mol Genet. 2014 Jul 15;23(14):3666-80; Davy G et al. Eur J Hum Genet. 2017 Oct; 25(10): 1147–1154). Since supporting evidence is conflicting at this time, the clinical significance of this alteration remains unclear. -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 14, 2023	This variant changes 1 nucleotide in exon 7 of the BRCA1 gene, creating a premature translation stop signal in the first codon of exon 7. The variant transcript is expected to undergo nonsense-mediated decay, resulting in an absent or non-functional protein product. There is a naturally occurring alternate transcript lacking the first 3 bp of exon 7 that may account for approximately one-third of total BRCA1 transcripts in normal tissues (PMID: 24569164, 28905878, 32133419). Because this truncation variant falls within the first 3 bp of exon 7, there is a possibility that the alternative splicing product could ameliorate the deleterious impact of this variant. However, this hypothesis has not been investigated in published functional studies. This variant has been detected in individuals with BRCA1-associated clinical features, as well as in unaffected individuals (communication with external laboratories). This variant has been observed in one family, and a multifactorial analysis based on co-occurrence with other pathogenic variant(s) and family history was not conclusive about the pathogenicity of this variant (PMID: 31131967). 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

Likely pathogenic, no assertion criteria provided

clinical testing

Sharing Clinical Reports Project (SCRP)

Dec 01, 2011

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.60	D
BayesDel_noAF	Pathogenic	0.62
Cadd	Pathogenic	40
Dann	Uncertain	1.0
Eigen	Pathogenic	0.96
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Uncertain	0.89	D
MutationTaster	Benign	1.0	A;A;A;A;A;A;A;A;A;A;D;D;D;D
Vest4		0.92
GERP RS		5.2

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.99
dbscSNV1_RF	Pathogenic	0.87
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: rs876659614; hg19: chr17-41251897;