17-43094569-C-T

Position:

• chr17-43094569-C-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.962G>A​(p.Trp321Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,872 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 (★★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: BRCA1 NM_007294.4 stop_gained
• Clinical Significance: Pathogenic reviewed by expert panel P:20 O:1
• Conservation: PhyloP100: 0.749

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 17-43094569-C-T is Pathogenic according to our data. Variant chr17-43094569-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 37712.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43094569-C-T is described in Lovd as [Pathogenic]. Variant chr17-43094569-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA1	NM_007294.4	c.962G>A	p.Trp321Ter	stop_gained	10/23	ENST00000357654.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA1	ENST00000357654.9	c.962G>A	p.Trp321Ter	stop_gained	10/23	1	NM_007294.4	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251402 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135866

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461872 Hom.: 0 Cov.: 34 AF XY: 0.00000275 AC XY: 2 AN XY: 727234

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: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:20 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:5 Other:1

not provided, no classification provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA1)	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Sep 07, 2012	- -
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, 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	Baylor Genetics	May 30, 2023	- -
Pathogenic, no assertion criteria provided	clinical testing	BRCAlab, Lund University	Mar 02, 2020	- -

not provided Pathogenic:5

Pathogenic, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The BRCA1 p.Trp321X variant was identified in 4 of 4476 proband chromosomes (frequency: 0.0009) from individuals or families with breast and ovarian cancer (Shattuck-Eidens 1997, Claus 2005, Belanger 2015, Simard 2007). The variant was also identified in dbSNP (ID: rs80357292) “With Pathogenic allele”, ClinVar (as pathogenic by ENIGMA, CIMBA, Invitae, GeneDx, Ambry Genetics, CHEO, Quest Diagnostics, GeneKor, SCARP, BIC), LOVD 3.0 (4x, functional affect is reported and concluded.), UMD-LSDB (10 records, as class 5, causal), BIC Database (23x reported), and ARUP Laboratories (as class 5 and-Definitely pathogenic). The variant was not identified in Genesight-COGR, Cosmic, MutDB, and Zhejiang Colon Cancer databases. The variant was identified in control databases in 1 of 246166 chromosomes at a frequency of 0.000004 in European population (Genome Aggregation Consortium Feb 27, 2017). The p.Trp321X variant leads to a premature stop codon at position 321, which is predicted to lead to a truncated or absent protein and loss of function.Loss of function variants of the BRCA1 gene are an established mechanism of disease in breast and ovarian cancer and is the type of variant expected to cause the disorder. In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 06, 2023	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; Observed in individuals with a personal or family history consistent with pathogenic variants in this gene (Shattuck-Eidens et al., 1997; Walsh et al., 2011; Belanger et al., 2015; Tung et al., 2016; Meric-Bernstam et al., 2016; Nguyen-Dumont et al., 2021); Not observed at significant frequency 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 1081G>A; This variant is associated with the following publications: (PMID: 25722380, 26659639, 9333265, 22535016, 25884701, 22006311, 10644434, 26787237, 27150160, 27376475, 26976419, 27836010, 16905680, 28503720, 25525159, 32719484, 32885271, 30078507, 29446198, 30720243, 30787465, 32467295, 29922827, 30257646, 28888541, 33804961) -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jun 25, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Aug 18, 2020	This nonsense variant causes the premature termination of BRCA1 protein synthesis. It has been reported in multiple individuals with hereditary breast and/or ovarian cancer in the published literature (PMIDs: 30257646 (2018), 29446198 (2018), 23772696 (2014), 22535016 (2012), 23199084 (2010), 16905680 (2007), 16683254 (2006), 16287141 (2005), 15728167 (2005), 15382066 (2004), and 9333265 (1997)). Based on the available information, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics and Genomics, Karolinska University Hospital	Sep 16, 2016	- -

Hereditary breast ovarian cancer syndrome Pathogenic:3

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	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 20, 2024	Variant summary: BRCA1 c.962G>A (p.Trp321*) results in a premature termination codon, predicted to cause an absence of protein due to nonsense mediated decay, which is a commonly known mechanism for disease. The variant allele was found at a frequency of 4e-06 in 251402 control chromosomes. c.962G>A has been reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer (example, Kroiss_2005). The following publication has been ascertained in the context of this evaluation (PMID: 16287141). ClinVar contains an entry for this variant (Variation ID: 37712). Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Oct 22, 2023	This sequence change creates a premature translational stop signal (p.Trp321*) 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 present in population databases (rs80357292, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with breast and/or ovarian cancer (PMID: 9333265, 10644434, 15382066, 16287141, 16683254, 22535016). This variant is also known as 1081G>A. ClinVar contains an entry for this variant (Variation ID: 37712). For these reasons, this variant has been classified as Pathogenic. -

Breast and/or ovarian cancer Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Jun 12, 2023	- -
Pathogenic, no assertion criteria provided	clinical testing	Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research	Feb 05, 2016	- -

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 08, 2022	The p.W321* pathogenic mutation (also known as c.962G>A), located in coding exon 9 of the BRCA1 gene, results from a G to A substitution at nucleotide position 962. This changes the amino acid from a tryptophan to a stop codon within coding exon 9. This mutation has been reported in multiple families affected with breast cancer (Shattuck-Eidens D et al. JAMA.1997;278(15):1242-50; Oros KK et al. Int J Cancer. 2004;112(3):411-9; Hoyer J et al. BMC Cancer 2018 Sep;18:926). This alteration has also been described as a French-Canadian founder mutation (Janaviius R. EPMA J 2010 Sep;1(3):397-412), and in a large, worldwide study of BRCA1/2 mutation positive families (Rebbeck TR et al. Hum. Mutat. 2018 05;39:593-620). Of note, this alteration is also designated 1081G>A in published literature. In addition to the clinical data presented in the 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Feb 28, 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 observed in individuals and families affected with breast, ovarian and peritoneal cancers (PMID: 9333265, 10644434, 15382066, 16287141, 16683254, 22006311, 22535016, 30257646) and it is described as a recurrent founder mutation in the French-Canadian population (PMID: 23199084). This variant has been identified in 1/251402 chromosomes 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. -

Tay-Sachs disease Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Mar 20, 2024

Variant summary: HEXA c.962G>A (p.Gly321Glu) results in a non-conservative amino acid change located in the Glycoside hydrolase family 20, catalytic domain (IPR015883) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251400 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.962G>A in individuals affected with Tay-Sachs Disease and no experimental evidence demonstrating its impact on protein function have 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 uncertain significance. -

not specified Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneKor MSA

Jul 01, 2016

- -

Long QT syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Mar 20, 2024

Variant summary: ANK2 c.962G>A (p.Arg321Gln) results in a 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 allele was found at a frequency of 0.00075 in 250854 control chromosomes in the gnomAD database, including 1 homozygotes. The observed variant frequency is approximately 111.82 fold of the estimated maximal expected allele frequency for a pathogenic variant in ANK2 causing Long QT Syndrome phenotype (6.7e-06), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.962G>A in individuals affected with Long QT Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (Benign/likely benign n=5, VUS n=1). Based on the evidence outlined above, the variant was classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	35
DANN	Uncertain	0.99
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Benign	0.69	D
MutationTaster	Benign	1.0	A;A;A;A;A;A;A;A;A;A;A;A;A;A
Vest4		0.79
ClinPred		0.74	D
GERP RS		3.0

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: rs80357292; hg19: chr17-41246586;