rs80357872

Positions:

chr17-43099807-TG-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_007294.4(BRCA1):c.514del(p.Gln172AsnfsTer62) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 1,613,276 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

BRCA1
NM_007294.4 frameshift

Scores

Not classified

Clinical Significance

Pathogenic reviewed by expert panel P:16

Conservation

PhyloP100: 1.24

Variant links:

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]

BRCA1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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 17-43099807-TG-T is Pathogenic according to our data. Variant chr17-43099807-TG-T is described in ClinVar as [Pathogenic]. Clinvar id is 55421.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43099807-TG-T is described in Lovd as [Pathogenic]. Variant chr17-43099807-TG-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA1	NM_007294.4 linkuse as main transcript	c.514del	p.Gln172AsnfsTer62	frameshift_variant	7/23	ENST00000357654.9	NP_009225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9 linkuse as main transcript	c.514del	p.Gln172AsnfsTer62	frameshift_variant	7/23	1	NM_007294.4	ENSP00000350283	P4	P38398-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152214

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251472

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135908

show subpopulations

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:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461062

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

726930

show subpopulations

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:

9.00e-7

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152214

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74358

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:16

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1

Pathogenic:7

Pathogenic, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Nov 23, 2009	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Apr 26, 2021	The BRCA1 c.514delC variant is classified as Pathogenic (PVS1, PM2_Supporting, PP5) This BRCA1 c.514delC variant is located in exon Missing Exon and is predicted to cause a shift in the reading frame at codon 172. This variant is absent from population databases (PM2). The variant has been reported in dbSNP (rs80357872) and has been reported as Pathogenic by other diagnostic laboratories (ClinVar Variation ID: 55421). It has not been reported in HGMD. literature: Finch et al., 2016, PMID:26219728, Wong-Brown et al., 2015, PMID:25682074, Ghiorzo et al., 2012, PMID:21989927, Miolo et al., 2009, PMID:19818148, Tai et al., 2007, PMID:18042939, Russo et al., 2007, PMID:17221156, Nanda et al., 2005, PMID:16234499, van Orsouw et al., 1999, PMID:10528853, Azzollini et al., 2016, PMID:27062684, Nedelcu et al., 2002, PMID:11938448, Lu et al., 2015, PMID:26689913, Huang et al., 2018, PMID:29625052, Fanale et al., 2020, PMID:32854451 -
Pathogenic, reviewed by expert panel	curation	Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	Apr 22, 2016	Variant allele predicted to encode a truncated non-functional protein. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 29, 2024	- -
Pathogenic, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA1)	Dec 30, 1999	- -
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, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The p.Gln172AsnfsX62 deletion variant has been previously reported in the literature in at least 2 of 178 proband chromosomes in individuals or families with pancreatic and breast cancer (Ghiorzo 2012, van Orsouw 1999). The variant was also reported in HGMD, the UMD (3x as causal) and in the BIC (23x as clinically important) databases. It is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 172 and leads to a premature stop codon 62 codons downstream. This alteration is then predicted to result in a truncated or absent protein and loss of function. Loss of function variants of the BRCA1 gene are an established mechanism of hereditary breast and ovarian cancer. In summary, based on the above information, this variant is classified as pathogenic. -

not provided

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jul 03, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	May 25, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 25, 2023	Frameshift 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 several Hereditary Breast and Ovarian Cancer families (van Orsouw et al., 1999; Tai et al., 2007; Ghiorzo et al., 2012; Finch et al., 2015; Incorvaia et al., 2020); 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 633delC; This variant is associated with the following publications: (PMID: 27157322, 26219728, 25682074, 17591842, 20682393, 32438681, 28888541, 10528853, 18042939, 17221156, 27376475, 27566247, 21989927, 30128899, 29922827, 29907814, 29337092, 29625052, 26689913, 32854451, 30787465, 36139606, 34178674, 33573335, 32380732) -

Hereditary breast ovarian cancer syndrome

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 10, 2024	Variant summary: BRCA1 c.514delC (p.Gln172AsnfsX62) 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 allele was found at a frequency of 4e-06 in 251472 control chromosomes. c.514delC has been reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome. 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. The following publications have been ascertained in the context of this evaluation (PMID: 27062684, 18042939, 25682074). ClinVar contains an entry for this variant (Variation ID: 55421). 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	Labcorp Genetics (formerly Invitae), Labcorp	Sep 21, 2023	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 55421). This variant is also known as 633delC. This premature translational stop signal has been observed in individual(s) with breast, ovarian and pancreatic cancer (PMID: 10528853, 17591842, 21989927, 25682074, 26219728). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Gln172Asnfs*62) 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). -

Hereditary cancer-predisposing syndrome

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 15, 2021	The c.514delC pathogenic mutation, located in coding exon 6 of the BRCA1 gene, results from a deletion of one nucleotide at nucleotide position 514, causing a translational frameshift with a predicted alternate stop codon (p.Q172Nfs*62). This mutation has been reported in multiple individuals and families affected with hereditary breast and ovarian cancer (HBOC) syndrome (van Orsouw NJ et al. J Med Genet. 1999 Oct;36(10):747-53; Nedelcu R et al. Eur. J. Hum. Genet. 2002 Feb;10(2):150-2; Nanda R et al. JAMA 2005 Oct;294(15):1925-33; Russo A et al. Breast Cancer Res. Treat. 2007 Nov;105(3):267-76; Tai YC et al. J Natl Cancer Inst. 2007 Dec;99(23):1811-4; Miolo G et al. BMC Cancer 2009 Oct;9:360; Ghiorzo P et al. Fam Cancer. 2012 Mar;11(1):41-7; Incorvaia L et al. Cancers (Basel), 2020 May;12; Fanale D et al. Cancers (Basel), 2020 Aug;12). Of note, this alteration is also designated as 633delC 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 deletes 1 nucleotide in exon 7 of the BRCA1 gene, creating a frameshift and premature translation stop signal. It is also known as 633delC according to the BIC nomenclature. This variant is expected to result in an absent or non-functional protein product. This variant has been observed in individuals with breast and/or ovarian cancer (PMID: 10528853, 17221156, 17591842, 25682074, 26219728) and pancreatic cancer (PMID: 21989927). This variant has been identified in 1/251472 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. -

Breast and/or ovarian cancer

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research

Dec 03, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

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Prediction

Splicing

Name

Calibrated prediction

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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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over