rs80357509

chr17-43092045-AT-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.3485del(p.Asp1162ValfsTer48) 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 1,613,954 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★★). Synonymous variant affecting the same amino acid position (i.e. D1162D) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: BRCA1 NM_007294.4 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:25 O:1
• Conservation: PhyloP100: 0.538

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 17-43092045-AT-A is Pathogenic according to our data. Variant chr17-43092045-AT-A is described in ClinVar as [Pathogenic]. Clinvar id is 37531.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43092045-AT-A is described in Lovd as [Pathogenic]. Variant chr17-43092045-AT-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA1	NM_007294.4	c.3485del	p.Asp1162ValfsTer48	frameshift_variant	10/23	ENST00000357654.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA1	ENST00000357654.9	c.3485del	p.Asp1162ValfsTer48	frameshift_variant	10/23	1	NM_007294.4	P4

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152200 Hom.: 0 Cov.: 32

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: 1 AN: 251278 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135808

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: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461754 Hom.: 0 Cov.: 39 AF XY: 0.00000138 AC XY: 1 AN XY: 727178

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: 0.00

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152200 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74356

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

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:25 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:10

Pathogenic, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Apr 16, 2014	- -
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	research	Center of Medical Genetics and Primary Health Care	Apr 08, 2020	ACMG Guidelines 2015 criteria The BRCA1 p.Asp1162Valfs variant is a known pathogenic variant also in exon 11 in a non-functional domain just before the BRSTCANCERI domain (S1180-1200Q aa) (PMID: 10198641) and in a mutational hotspot with 34 pathogenic variants (PM1 Pathogenic Moderate). The deletion causes a frameshift, which changes an Aspartic Acid to a Valine at codon 1162, and creates a premature stop codon at position 48 of the new reading frame. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay which is an established disease mechanism in hereditary breast and ovarian cancer (PVS1 Pathogenic Very Strong). The allele frequency in GnomAD exomes is 0.00000398 which is less the threshold 0.0001 for recessive gene BRCA1, and the variant is not found in GnomAD genomes (PM2 Pathogenic Moderate). The variant has been classified as pathogenic by the ClinGen-approved ENIGMA expert panel (ClinVar SCV000299952.2) (PP5 Pathogenic Supporting). 1 pathogenic prediction from GERP versus no benign prediction supports its deleterious effect (PP3 Pathogenic Supporting). In this study the variant Asp1162Valfs was found in a 51- year-old female with unilateral breast cancer and strong family history. Therefore, this variant was classified as a Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Unidad Asesoramiento Genetico Oncologico Falp, Instituto Oncologico Fundacion Arturo Lopez Perez	Aug 01, 2023	- -
Pathogenic, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA1)	May 29, 2002	- -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 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	Baylor Genetics	Jun 04, 2021	- -
Pathogenic, no assertion criteria provided	clinical testing	BRCAlab, Lund University	Mar 02, 2020	- -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not provided Pathogenic:7

Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jan 24, 2022	This frameshift variant alters the translational reading frame of the BRCA1 mRNA and 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 with a personal or family history of breast and/or ovarian cancer (PMIDs: 28324225 (2017), 26681312 (2015), 25452441 (2015), 23192404 (2013), 9150151 (1997)). Based on the available information, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 07, 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 hereditary breast and ovarian cancer families, and is a common variant in Finnish and Dutch populations (Peelen et al., 1997; Vehmanen et al., 1997; Syrjakoski et al., 2000; Janavicius et al., 2010; Brohet et al., 2014); 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 3604delA; This variant is associated with the following publications: (PMID: 23199084, 16683254, 30927251, 29922827, 28888541, 9667259, 24285858, 26681312, 9361038, 10995809, 25452441, 28324225, 11773283, 30720243, 30322717, 9150151, 11597388, 33558524, 24010542, 34697415) -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2023	BRCA1: PVS1, PS4:Moderate, PP1 -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Aug 28, 2021	The BRCA1 c.3485delA; p.Asp1162ValfsTer48 variant (rs803575090), also published as 3604delA, is reported in the literature in several individuals and families with hereditary breast and ovarian cancer (Carter 2018, Couch 2015, Meisel 2017, Susswein 2016). The variant is reported in the ClinVar database (Variation ID: 37531) and is only observed on one allele in the Genome Aggregation Database, indicating it is not a common polymorphism. This variant causes a frameshift by deleting a single nucleotide, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. References: Carter NJ et al. Germline pathogenic variants identified in women with ovarian tumors. Gynecol Oncol. 2018 Dec;151(3):481-488. PMID: 30322717. Couch FJ et al. Inherited mutations in 17 breast cancer susceptibility genes among a large triple-negative breast cancer cohort unselected for family history of breast cancer. J Clin Oncol. 2015 Feb 1;33(4):304-11. PMID: 25452441. Meisel C et al. Spectrum of genetic variants of BRCA1 and BRCA2 in a German single center study. Arch Gynecol Obstet. 2017 May;295(5):1227-1238. PMID: 28324225. Susswein LR et al. Pathogenic and likely pathogenic variant prevalence among the first 10,000 patients referred for next-generation cancer panel testing. Genet Med. 2016 Aug;18(8):823-32. PMID: 26681312. -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Dec 02, 2022	- -

Hereditary breast ovarian cancer syndrome Pathogenic:5 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 27, 2017	The p.Asp1162fs variant in BRCA1 has been reported in >30 individuals with BRCA1 -associated cancers (Peelen 1997, Breast Cancer Information Core (BIC) database) and was absent from large population studies. This variant is predicted to caus e a frameshift, which alters the protein?s amino acid sequence beginning at posi tion 1162 and leads to a premature termination codon 48 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Hete rozygous loss of function of function of the BRCA1 gene is an established diseas e mechanism in hereditary breast and ovarian cancer (HBOC). In addition, this va riant was classified as Pathogenic on September 8, 2016 by the ClinGen-approved ENIGMA expert panel (ClinVar SCV000299952.2). In summary, the p.Asp1162fs varian t meets criteria to be classified as pathogenic for HBOC in an autosomal dominan t manner. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 28, 2023	This sequence change creates a premature translational stop signal (p.Asp1162Valfs*48) 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 (rs80357509, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with breast and/or ovarian cancer (PMID: 9150151, 16683254, 24010542, 25452441, 26681312). This variant is also known as 3604delA, c.3625delA, and 3741delA. ClinVar contains an entry for this variant (Variation ID: 37531). 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	Aug 06, 2021	Variant summary: BRCA1 c.3485delA (p.Asp1162ValfsX48) 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 allele was found at a frequency of 4e-06 in 251278 control chromosomes. c.3485delA has been reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (e.g. Vehmanen_1997, Peelen_1997, Judkins_2005, Rummel_2013). These data indicate that the variant is very likely to be associated with disease. Twelve 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	Curoverse	Aug 01, 2015	Frameshifts in BRCA1 are considered pathogenic, and this is a BRCA1 Asp1162Val frameshift variant in exon 10 -
Pathogenic, no assertion criteria provided	research	Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	Jan 31, 2014	- -
not provided, no classification provided	phenotyping only	GenomeConnect - Invitae Patient Insights Network	-	Variant interpreted as Pathogenic and reported on 07-16-2020 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 21, 2021	The c.3485delA pathogenic mutation, located in coding exon 9 of the BRCA1 gene, results from a deletion of one nucleotide at nucleotide position 3485, causing a translational frameshift with a predicted alternate stop codon (p.D1162Vfs*48). This mutation has been reported in multiple hereditary breast and ovarian cancer (HBOC) families (Peelen T et al. Am. J. Hum. Genet., 1997 May;60:1041-9; Vehmanen P et al. Hum. Mol. Genet., 1997 Dec;6:2309-15; Frank TS et al. J. Clin. Oncol., 1998 Jul;16:2417-25; Ligtenberg MJ et al. Br. J. Cancer, 1999 Mar;79:1475-8; Sarantaus L et al. Eur. J. Hum. Genet., 2001 Jun;9:424-30; Verhoog LC et al. Eur. J. Cancer, 2001 Nov;37:2082-90; Meindl A et al. Int. J. Cancer, 2002 Feb;97:472-80; Meisel C et al. Arch. Gynecol. Obstet., 2017 May;295:1227-1238; Carter NJ et al. Gynecol Oncol, 2018 12;151:481-488; Nurmi A et al. Int J Cancer, 2019 11;145:2692-2700; Moradian MM et al. Hum Genome Var, 2021 Feb;8:9; Dorling et al. N Engl J Med. 2021 02;384:428-439). Of note, this alteration is also designated as 3604delA 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	Mar 21, 2022	This variant deletes 1 nucleotide in exon 10 of the BRCA1 gene, creating a frameshift and 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 and families affected with breast and/or ovarian cancer (PMID: 9150151, 9361038, 9667259, 10995809, 16683254, 24285858, 25452441, 26681312, 28324225, 30322717, 30927251). This variant has been identified in 81 families among the CIMBA participants (PMID: 29446198) (https://cimba.ccge.medschl.cam.ac.uk/). A large breast cancer case-control study (PMID: 33471991) has reported this variant in 5/60461 cases and 0/53461 controls. This variant has been identified in 1/251278 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. -

Familial cancer of breast Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare

-

- -

Computational scores

Source: dbNSFP v4.3

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: rs80357509; hg19: chr17-41244062;