rs80356992

Positions:

• chr17-43074394-G-A
• chr17-43074394-G-C

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.4612C>T​(p.Gln1538*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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)
• Consequence: BRCA1 NM_007294.4 stop_gained
• Clinical Significance: Pathogenic reviewed by expert panel P:11
• Conservation: PhyloP100: 0.418

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 17-43074394-G-A is Pathogenic according to our data. Variant chr17-43074394-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 55239.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43074394-G-A is described in Lovd as [Pathogenic]. Variant chr17-43074394-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA1	NM_007294.4	c.4612C>T	p.Gln1538*	stop_gained	14/23	ENST00000357654.9	NP_009225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9	c.4612C>T	p.Gln1538*	stop_gained	14/23	1	NM_007294.4	ENSP00000350283.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:11

Revision: reviewed by expert panel

Submissions by phenotype

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

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	Baylor Genetics	Oct 22, 2023	- -
Pathogenic, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	May 01, 2012	- -
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, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA1)	May 29, 2002	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	May 02, 2019	This variant causes the premature termination of BRCA1 protein synthesis. It has been reported in in affected individuals with breast and/or ovarian cancer in the published literature (PMIDs: 9452076 (1998), 11920621 (2002), 25151137 (2015), 29339979 (2018) and 29470806 (2018)). Based on the available information, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 28, 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; Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Not observed at significant frequency in large population cohorts (gnomAD); Also known as 4731C>T; This variant is associated with the following publications: (PMID: 21720365, 9452076, 11920621, 25525159, 26187060, 24578176, 25151137, 27221827, 19298662, 29339979, 30787465, 29470806, 31214711, 32410793, 29446198, 34917121, 30720243, 31825140, 30322717, 33948387) -

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jan 15, 2020	This variant changes 1 nucleotide in exon 14 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 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	Dec 21, 2021	The p.Q1538* pathogenic mutation (also known as c.4612C>T), located in coding exon 13 of the BRCA1 gene, results from a C to T substitution at nucleotide position 4612. This changes the amino acid from a glutamine to a stop codon within coding exon 13. This mutation has been reported in multiple individuals and families with hereditary breast and ovarian cancer (HBOC) (Tartaglini E et al. Hum. Mutat., 1998;Suppl 1:S163-6; De Leon Matsuda ML et al. Int. J. Cancer, 2002 Apr;98:596-603; Young SR et al. BMC Cancer, 2009 Mar;9:86; Guan Y et al. Fam Cancer, 2015 Mar;14:9-18; Heramb C et al. Hered Cancer Clin Pract, 2018 Jan;16:3; Rebbeck TR et al. Hum Mutat, 2018 05;39:593-620; Singh J et al. Breast Cancer Res Treat, 2018 Jul;170:189-196; Carter NJ et al. Gynecol Oncol, 2018 12;151:481-488; Wang N et al. Chin J Cancer Res, 2020 Apr;32:149-162). This mutation has also been reported with a carrier frequency of 0.00013 in 7636 unselected prostate cancer patients and absent in 12366 male controls of Japanese ancestry (Momozawa Y et al. J Natl Cancer Inst, 2020 04;112:369-376). Of note, this alteration is also designated as 4731C>T and Q1538X 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. -

Hereditary breast ovarian cancer syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 12, 2020	Variant summary: BRCA1 c.4612C>T (p.Gln1538X) 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. The variant was absent in 251362 control chromosomes (gnomAD). c.4612C>T has been reported in the literature in multiple individuals affected with Hereditary Breast and Ovarian Cancer (e.g. Rebbeck_2018, DeLeonMatsuda_2002, Singh_2018). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six ClinVar submitters (evaluation after 2014) including one expert panel (ENIGMA) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 25, 2023	This sequence change creates a premature translational stop signal (p.Gln1538*) 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 clinical features of hereditary breast and ovarian cancer syndrome (PMID: 9452076, 11920621, 25151137, 29446198, 29470806). This variant is also known as 4731C>T. ClinVar contains an entry for this variant (Variation ID: 55239). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
CADD	Pathogenic	34
DANN	Benign	0.94
Eigen	Benign	-0.072
Eigen_PC	Benign	-0.40
FATHMM_MKL	Benign	0.064	N
Vest4		0.86
GERP RS		2.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs80356992; hg19: chr17-41226411; COSMIC: COSV58785729; COSMIC: COSV58785729;