rs80357727

chr17-43091488-CCT-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.4041_4042del(p.Gly1348AsnfsTer7) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,214 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. R1347R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: BRCA1 NM_007294.4 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:22
• Conservation: PhyloP100: 2.03

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 17-43091488-CCT-C is Pathogenic according to our data. Variant chr17-43091488-CCT-C is described in ClinVar as [Pathogenic]. Clinvar id is 55082.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43091488-CCT-C is described in Lovd as [Pathogenic]. Variant chr17-43091488-CCT-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA1	NM_007294.4	c.4041_4042del	p.Gly1348AsnfsTer7	frameshift_variant	10/23	ENST00000357654.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA1	ENST00000357654.9	c.4041_4042del	p.Gly1348AsnfsTer7	frameshift_variant	10/23	1	NM_007294.4	P4

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152214 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

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: 0.00

Gnomad OTH AF: 0.00

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152214 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74362

Gnomad4 AFR AF: 0.0000241

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: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:22

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:8

Pathogenic, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Nov 30, 2011	- -
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	research	deCODE genetics, Amgen	Jul 21, 2023	The variant NM_007294.4:c.4041_4042del (chr17:430914889) in BRCA1 was detected in 4 heterozygotes out of 58K WGS Icelanders (MAF= 0,003%). This variant has been reported in ClinVar previously as pathogenic. Based on ACMG criteria (PVS1, PP5) this variant classifies as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	University of Washington Department of Laboratory Medicine, University of Washington	Nov 20, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Mar 03, 2023	Criteria applied: PVS1, PS4, PM2_SUP -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Nov 15, 2022	- -
Pathogenic, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA1)	May 29, 2002	- -
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. -

not provided Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 18, 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 individuals with a personal or family history consistent with pathogenic variants in this gene (Eccles et al., 1998; Kang et al., 2002; Laitman et al., 2011; Kim et al., 2012; Kwon et al., 2018; Mehta et al., 2018; Ryu et al., 2019); 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 4160_4161del; This variant is associated with the following publications: (PMID: 23697973, 9649133, 25330149, 26843898, 22864640, 30555256, 28111427, 27488874, 30350268, 17921118, 19016756, 22006311, 12204006, 25483746, 22798144, 27083178, 26187060, 20960228, 26845104, 28152038, 28724667, 30352249, 30309222, 30702160, 33726785, 31825140, 32101877, 34645131, 28888541) -
Pathogenic, criteria provided, single submitter	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Feb 23, 2021	PVS1, PM2, PS4 -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jul 17, 2020	The BRCA1 c.4041_4042del (p.Gly1348Asnfs*7) variant alters the translational reading frame of the BRCA1 mRNA and causes the premature termination of BRCA1 protein synthesis. This variant has been reported in the published literature in individuals affected with breast cancer and/or ovarian cancer (PMID: 9649133 (1998), 27488874 (2017), 25330149 (2015), 23697973 (2012)). Based on the available information, this variant is classified as pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneKor MSA	Jan 01, 2020	This is a deletion of 2 base pairs, which results in frameshift and creation of a stop codon 7 amino acid residues later. It is expected to result in an absent or disrupted protein product. Truncating variants in BRCA1 are known to be pathogenic. This variant has been described in the literature as 4160delAG. -

Hereditary breast ovarian cancer syndrome Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 09, 2022	Variant summary: BRCA1 c.4041_4042delAG (p.Gly1348AsnfsX7) 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 251088 control chromosomes. c.4041_4042delAG has been reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (example, Walsh_2011, Troudi_2007, Sugano_2008, Kim_2012, Eccles_1998, Judkins_2005). These data indicate that the variant is very likely to be associated with disease. Multiple clinical diagnostic laboratories, an expert panel (ENIGMA) and a consortium (CIMBA) have submitted clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 08, 2023	This sequence change creates a premature translational stop signal (p.Gly1348Asnfs*7) 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: 9649133, 12204006, 23697973, 25330149, 25418591, 27083178). ClinVar contains an entry for this variant (Variation ID: 55082). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Department of Pathology and Molecular Medicine, Queen's University	Apr 20, 2017	- -
Pathogenic, no assertion criteria provided	research	Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	Jan 31, 2014	- -

Hereditary cancer-predisposing syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Nov 01, 2023	This variant deletes 2 nucleotides in exon 10 of the BRCA1 gene, creating a frameshift and premature translation stop signal. This variant is also known as 4158delAG, 4159delGA and 4160delAG 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 over ten unrelated individuals affected with breast or ovarian cancer (PMID: 9649133, 12204006, 19016756, 22006311, 23697973, 25330149, 25418591, 27083178, 27488874, 29673794, 30555256, 32101877; Color internal data). 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. Based on the available evidence, this variant is classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	curation	Sema4, Sema4	Nov 15, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Jan 18, 2022	The c.4041_4042delAG pathogenic mutation, located in coding exon 9 of the BRCA1 gene, results from a deletion of two nucleotides at nucleotide positions 4041 to 4042, causing a translational frameshift with a predicted alternate stop codon (p.G1348Nfs*7). This mutation has been reported in multiple individuals/families with hereditary breast and ovarian cancer (HBOC) syndrome (Eccles DM et al. Br. J. Cancer. 1998 Jun;77:2199-203; Troudi W et al. J Hum Genet, 2007 Oct;52:915-920; Kim H et al. Breast Cancer Res. Treat. 2012 Aug;134:1315-26; Laitman Y et al. Breast Cancer Res. Treat. 2011 Jun;127:489-95; Fourati A et al. Bull Cancer. 2014 Nov;101:E36-40; Kluska A et al. BMC Med Genomics, 2015 May;8:19; Cybulski C et al. Clin. Genet. 2015 Oct;88:366-70; Riahi A et al. Breast Cancer, 2017 Mar;24:238-244; Eoh KJ et al. Cancer Res Treat. 2017 Apr;49(2):408-415; Park JS et al. Cancer Res Treat, 2017 Oct;49:1012-1021; Sun J et al. Clin Cancer Res, 2017 Oct;23:6113-6119; Mehta A et al. Cancer Manag Res, 2018 Nov;10:6505-6516; Ryu JM et al. Breast Cancer Res Treat, 2019 Jan;173:385-395; Wu H et al. Hum Hered, 2019 Feb;84:160-169). Of note, this alteration is also designated as c.4041delAG, 4158delAG and 4160delAG 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. -

Familial cancer of breast;C2676676:Breast-ovarian cancer, familial, susceptibility to, 1;C3280442:Pancreatic cancer, susceptibility to, 4;C4554406:Fanconi anemia, complementation group S Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Nov 24, 2021

- -

Familial cancer of breast Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

Center for Precision Medicine, Meizhou People's Hospital

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Computational scores

Source: dbNSFP v4.3

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: rs80357727; hg19: chr17-41243505;