17-43092667-G-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_007294.4(BRCA1):c.2864C>A(p.Ser955Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,832 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★★). Synonymous variant affecting the same amino acid position (i.e. S955S) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: BRCA1 NM_007294.4 stop_gained
• Clinical Significance: Pathogenic reviewed by expert panel P:15
• Conservation: PhyloP100: 0.891

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 18 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
• PP5: Variant 17-43092667-G-T is Pathogenic according to our data. Variant chr17-43092667-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 54701.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43092667-G-T is described in Lovd as [Pathogenic]. Variant chr17-43092667-G-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA1	NM_007294.4	c.2864C>A	p.Ser955Ter	stop_gained	10/23	ENST00000357654.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA1	ENST00000357654.9	c.2864C>A	p.Ser955Ter	stop_gained	10/23	1	NM_007294.4	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461832 Hom.: 0 Cov.: 48 AF XY: 0.00000275 AC XY: 2 AN XY: 727210

Gnomad4 AFR exome AF: 0.0000299

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: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:15

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:8

Pathogenic, reviewed by expert panel	curation	Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	Sep 08, 2016	Variant allele predicted to encode a truncated non-functional protein. -
Pathogenic, criteria provided, single submitter	clinical testing	Department of Medical Genetics, Oslo University Hospital	Apr 21, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	Oct 02, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Jul 19, 2023	This variant changes 1 nucleotide in exon 10 of the BRCA1 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in several individuals affected with breast cancer (PMID: 17925560, 19805903, 20104584, 21614564, 22034289, 30350268) and in other suspected hereditary breast and ovarian cancer families (PMID: 16030099, 18465347, 23233716, 29446198, 31209999). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of BRCA1 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA1)	Feb 20, 2004	- -
Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Dec 28, 2015	- -
Pathogenic, no assertion criteria provided	clinical testing	Pathway Genomics	Nov 06, 2014	- -
Pathogenic, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Sep 14, 2011	- -

Hereditary breast ovarian cancer syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 15, 2019	Variant summary: BRCA1 c.2864C>A (p.Ser955X) 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. The variant was absent in 251560 control chromosomes. c.2864C>A has been reported in the literature in multiple individuals affected with Hereditary Breast and Ovarian Cancer (including Borg_2010, Fackenthal_2012, Heramb_2018, Litton_2011, Thomassen_2008, Vaidyanathan_2009, Vogel_2007, Weitzel_2005). These data indicate that the variant is very likely to be associated with disease. Eight 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 pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, no assertion criteria provided	research	Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	Jan 31, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 02, 2024	This sequence change creates a premature translational stop signal (p.Ser955*) 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). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with personal or family history of breast and/or ovarian cancer (PMID: 16030099, 19805903, 20104584, 26187060, 29339979, 29446198). This variant is also known as 2983C>A. ClinVar contains an entry for this variant (Variation ID: 54701). For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 21, 2022	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; Not observed in large population cohorts (gnomAD); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as 2983C>A; Observed in multiple individuals with personal and/or family history of breast and/or ovarian cancer and has been reported as a recurrent pathogenic variant in the Hispanic population (Weitzel 2005, Vogel 2007, Thomassen 2008, Vaidyanathan 2009, Borg 2010, Fackenthal 2012); This variant is associated with the following publications: (PMID: 26187060, 24312913, 18465347, 25525159, 27286788, 20104584, 26564481, 19805903, 21913181, 25371446, 16030099, 23233716, 22034289, 17925560, 29339979, 29446198) -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Oct 06, 2021	This nonsense variant causes the premature termination of BRCA1 protein synthesis. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in individuals/families with breast and/or ovarian cancer in the published literature (PMIDs: 29446198 (2018), 19805903 (2009), 17925560 (2007), 16030099 (2005)). Based on the available information, this variant is classified as pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Apr 27, 2023	This variant changes 1 nucleotide in exon 10 of the BRCA1 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in several individuals affected with breast cancer (PMID: 17925560, 19805903, 20104584, 21614564, 22034289, 30350268) and in other suspected hereditary breast and ovarian cancer families (PMID: 16030099, 18465347, 23233716, 29446198, 31209999). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of BRCA1 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Oct 04, 2021	The p.S955* pathogenic mutation (also known as c.2864C>A), located in coding exon 9 of the BRCA1 gene, results from a C to A substitution at nucleotide position 2864. This changes the amino acid from a serine to a stop codon within coding exon 9. This alteration has been identified in numerous breast/ovarian cohorts from North American, European, Hispanic, African, and Indian families (Weitzel JN et al. Cancer Epidemiol Biomarkers Prev. 2005;14(7):1666-71; Vogel KJ et al. J. Clin. Oncol., 2007 Oct;25:4635-41; Vaidyanathan, K et al. J Biosci. 2009 Sep;34(3):415-22; Borg A et al. Hum. Mutat., 2010 Mar;31:E1200-40; Kwong A et al. J Med Genet, 2016 Jan;53:15-23; Heramb C et al. Hered Cancer Clin Pract, 2018 Jan;16:3; Rebbeck TR et al. Hum. Mutat., 2018 May;39:593-620; Ryu JM et al. Breast Cancer Res Treat, 2019 Jan;173:385-395). Of note, this alteration is also designated as 2983C>A in the published literature. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.29
Cadd	Pathogenic	35
Dann	Uncertain	0.99
Eigen	Uncertain	0.27
Eigen_PC	Benign	-0.013
FATHMM_MKL	Benign	0.28	N
MutationTaster	Benign	1.0	A;A;A;A;A;A;N;N;N;N;N;N;N;N
Vest4		0.83
GERP RS		3.9

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: rs80357295; hg19: chr17-41244684;