17-43049174-G-A

Position:

• chr17-43049174-G-A

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.5353C>T​(p.Gln1785Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,842 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: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: BRCA1 NM_007294.4 stop_gained
• Clinical Significance: Pathogenic reviewed by expert panel P:15 O:1
• Conservation: PhyloP100: 1.99

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 17-43049174-G-A is Pathogenic according to our data. Variant chr17-43049174-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 55546.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43049174-G-A is described in Lovd as [Pathogenic]. Variant chr17-43049174-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.5353C>T	p.Gln1785Ter	stop_gained	21/23	ENST00000357654.9	NP_009225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9	c.5353C>T	p.Gln1785Ter	stop_gained	21/23	1	NM_007294.4	ENSP00000350283	P4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461842 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727226

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: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:15 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:7 Other:1

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	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
not provided, no classification provided	in vitro	Brotman Baty Institute, University of Washington	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	May 23, 2012	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jun 26, 2022	- -
Pathogenic, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA1)	Jun 26, 1998	- -
Pathogenic, criteria provided, single submitter	clinical testing	Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	Oct 02, 2015	- -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Feb 27, 2020	This nonsense variant causes the premature termination of BRCA1 protein synthesis. In addition, it has been reported in several affected individuals and families with breast and/or ovarian cancer in the published literature (PMIDs: 16683254 (2006), 17925560 (2007), 27157322 (2016), 29446198 (2018), 30093976 (2018), and 30702160 (2019)). Based on the available information, this variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 24, 2022	PM2, PS3_supporting, PS4_supporting, PVS1 -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 30, 2024	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 5472C>T; This variant is associated with the following publications: (PMID: 16683254, 30128899, 34413315, 32438681, 17925560, 26187060, 29681614, 27157322, 30702160, 30093976, 31825140, 29446198, 30720243, 30875412, 30787465, 30209399, 35837282, 28888541) -

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Apr 12, 2021	This variant changes 1 nucleotide in exon 21 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 individuals affected with hereditary breast and/or ovarian cancer (PMID: 16683254, 17925560, 26187060, 29681614, 30128899, 30702160, 30875412). 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	Jun 30, 2023	The p.Q1785* pathogenic mutation (also known as c.5353C>T), located in coding exon 20 of the BRCA1 gene, results from a C to T substitution at nucleotide position 5353. This changes the amino acid from a glutamine to a stop codon within coding exon 20. This mutation has been identified in multiple hereditary breast and ovarian cancer (HBOC) families (van der Hout AH et al. Hum. Mutat. 2006 Jul;27(7):654-66; Vogel KJ et al. J. Clin. Oncol. 2007 Oct;25:4635-41; Kwong A et al. J Mol Diagn, 2016 07;18:580-94; Lilyquist J et al. Gynecol. Oncol., 2017 11;147:375-380; Chan GHJ et al. Oncotarget, 2018 Jul;9:30649-30660; Liang Y et al. Med. Sci. Monit., 2018 Apr;24:2465-2475; Rebbeck TR et al. Hum. Mutat., 2018 05;39:593-620; Bhaskaran SP et al. Int. J. Cancer, 2019 08;145:962-973) and one functional study found that this nucleotide substitution is deleterious in a high throughput genome editing haploid cell survival assay (Findlay GM et al. Nature, 2018 10;562:217-222). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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	Labcorp Genetics (formerly Invitae), Labcorp	Dec 06, 2023	This sequence change creates a premature translational stop signal (p.Gln1785*) 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 hereditary breast and/or ovarian cancer (PMID: 16683254, 17925560, 27157322). This variant is also known as 5472C>T. ClinVar contains an entry for this variant (Variation ID: 55546). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 02, 2020	Variant summary: BRCA1 c.5353C>T (p.Gln1785X) 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 251446 control chromosomes (gnomAD). c.5353C>T has been reported in the literature in multiple individuals affected with Hereditary Breast and Ovarian Cancer (e.g. Marchetti_2018, Rebbeck_2018, van der Hout_2006). These data indicate that the variant is very likely to be associated with disease. Eight ClinVar submitters including an expert panel (ENIGMA) (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Malignant tumor of breast Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The p.Gln1785X variant was identified in 2 of 1018 proband chromosomes (frequency: 0.002) from individuals or families with breast or ovarian cancer (van der Hout 2003, Vogel 2007). In one study this variant was included among other deleterious variants found to cause loss of FHIT (fragile histidine triad) protein expression in matched tumour case-controls, suggesting that the BRCA1 repair pathway is important in protection of chromosomal fragile sites (Turner 2002). The variant was identified in dbSNP (ID: rs80356969) “With pathogenic allele”, HGMD, the BIC database (4X with pathogenic clinical importance), 2X in Clinvar (1X by multiple submitters: the Sharing Clinical Reports Project (SCRP) (submitted within the ClinVar database and derived from Myriad reports) as pathogenic, and BIC as pathogenic; and, 1X by Invitae, classification not provided). The p.Gln1785X variant leads to a premature stop codon at position 1785, 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 hereditary 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	37
DANN	Uncertain	0.99
Eigen	Pathogenic	0.77
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Uncertain	0.82	D
MutationTaster	Benign	1.0	A;A;A;A;A;A;A;A;A;A;A;A;A;D
Vest4		0.91
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs80356969; hg19: chr17-41201191;