rs80358343

Positions:

• chr17-43067662-TGTG-T

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1 PM2 PM4_Supporting PP5_Very_Strong

The NM_007294.4(BRCA1):​c.5017_5019del​(p.His1673del) variant causes a inframe deletion change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 30)
• Consequence: BRCA1 NM_007294.4 inframe_deletion
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:14 U:2
• Conservation: PhyloP100: 2.60

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 13 ACMG points.

• PM1: In a domain BRCT 1 (size 94) in uniprot entity BRCA1_HUMAN there are 74 pathogenic changes around while only 17 benign (81%) in NM_007294.4
• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_007294.4. Strenght limited to Supporting due to length of the change: 1aa.
• PP5: Variant 17-43067662-TGTG-T is Pathogenic according to our data. Variant chr17-43067662-TGTG-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 55355.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA1	NM_007294.4	c.5017_5019del	p.His1673del	inframe_deletion	16/23	ENST00000357654.9	NP_009225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9	c.5017_5019del	p.His1673del	inframe_deletion	16/23	1	NM_007294.4	ENSP00000350283	P4

Frequencies

GnomAD3 genomes Cov.: 30

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

GnomAD4 genome Cov.: 30

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:14 Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:6 Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Apr 25, 2022	- -
Uncertain significance, flagged submission	clinical testing	Breast Cancer Information Core (BIC) (BRCA1)	Apr 05, 1999	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Aug 03, 2022	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	3billion	Feb 23, 2023	The variant is not observed in the gnomAD v2.1.1 dataset. This variant was predicted to result in inframe deletion located in a non-repeat region and is predicted to change the length of the protein and disrupt normal protein function. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000055355). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, no assertion criteria provided	clinical testing	Department of Medical and Surgical Sciences, University of Bologna	Sep 01, 2023	PS3(Strong)+PM3(Supporting)+PP4(Very Strong) according to ACMG/AMP classification guidelines specified for BRCA1 & BRCA2 (Classification Criteria V1.0.0 2023-09-08 - https://cspec.genome.network/cspec/ui/svi/affiliation/50087) (PMID: 38160042) -
Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Feb 25, 2021	Criteria applied: PS4_STR, PM4_SUP, PM2_SUP -
Likely pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

not provided Pathogenic:3 Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Aug 04, 2020	Not found in the total gnomAD dataset, and the data is high quality. Found in at least one patient with expected phenotype for this gene. Located in potentially critical domain of the protein. Segregation with disease in unaffected individuals from multiple families. -
Uncertain significance, flagged submission	clinical testing	GeneDx	Oct 17, 2017	This in-frame deletion of 3 nucleotides in BRCA1 is denoted c.5017_5019delCAC at the cDNA level and p.His1673del (H1673del) at the protein level. The normal sequence, with the bases that are deleted in brackets, is ACAC[delCAC]ATCA. This deletion of a single Histidine residue occurs at a position that is not conserved and is located in the BRCT1 domain as well as a region known to interact with multiple other proteins (Paul 2014, UniProt). This variant has been observed in individuals with breast and/or ovarian cancer (Lim 2009, Ryu 2017, Zuntini 2017). Protein modeling suggests that this residue may play a role in protein stability (Coquelle 2011). Since in-frame deletions may or may not inhibit proper protein functioning, the clinical significance of this finding remains unclear at this time and we consider BRCA1 His1673del to be a variant of uncertain significance. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	May 09, 2022	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	May 01, 2024	The BRCA1 c.5017_5019del; p.His1673del variant (rs80358343; ClinVar Variation ID: 55355) has been described in the literature in multiple individuals and families with breast and ovarian cancer (Bang 2022), with some families showing incomplete co-segregation of the variant with disease (Zuntini 2017). This variant was found in trans with a pathogenic variant in an infant with Fanconi anemia (Borlin 2022). This variant is absent from the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. This variant deletes a single histidine residue leaving the rest of the predicted protein in-frame. Based on available information, this variant is considered to be likely pathogenic. References: Bang YJ et al. Comprehensive clinical characterization of patients with BRCA1: c.5017_5019del germline variant. Ann Surg Treat Res. 2022 Dec;103(6):323-330. PMID: 36601340. Borlin PR et al. Cancer in children with biallelic BRCA1 variants and Fanconi anemia-like features: Report of a malignant brain tumor in a young child. Pediatr Blood Cancer. 2022 Oct;69(10):e29680. PMID: 35373906. Zuntini R et al. BRCA1 p.His1673del is a pathogenic mutation associated with a predominant ovarian cancer phenotype. Oncotarget. 2017 Apr 4;8(14):22640-22648. PMID: 28186987. -

Hereditary breast ovarian cancer syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 25, 2024	This variant, c.5017_5019del, results in the deletion of 1 amino acid(s) of the BRCA1 protein (p.His1673del), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with BRCA1-related conditions (PMID: 11802209, 18092194, 19499246, 27062684, 28186987, 34645131, 36601340; Invitae). It has also been observed to segregate with disease in related individuals. This variant is also known as 5136delCAC. ClinVar contains an entry for this variant (Variation ID: 55355). Based on a multifactorial likelihood algorithm using genetic, in silico, and/or statistical data, this variant has been determined to have a high probability of being pathogenic (PMID: 28186987). For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	curation	German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne	Jan 18, 2024	. According to the ClinGen ENIGMA BRCA1 v1.0.0 criteria we chose these criteria: PM2 (supporting pathogenic): Absent from gnomAD, PM3 (medium pathogenic): Borlin 2022 (PMID: 35373906): 1 Pat. comp. het. +c.1116G>A [p.(Trp372*)]; 2 months severe growth retardation+dysmorphic features+hyperpigmented, 13 months CNS tumor; MMC-induced chromosomal breakage analysis in peripheral blood lymphocytes showed strongly reduced proliferation upon stimulation, but no evidence of increased chromosomal breakage; phenotype: cancer diagnosis ≤5yr + FA physical features score: 2 = moderate, PP1 (strong pathogenic): Among these, co-segregation in the 4 pedigrees with multiple members tested (the largest one is shown in Figure ​Figure2)2) resulted in a combined odds in favor of causality of 16.1:1. Parsons et al. Segregation LR=17.557504599 -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 27, 2024	Variant summary: BRCA1 c.5017_5019delCAC (p.His1673del) results in an in-frame deletion that is predicted to remove 1 amino acid from the encoded protein. The variant was absent in 252158 control chromosomes (gnomAD). c.5017_5019delCAC has been reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (e.g. Zuntini_2017, Bang_2022). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 11802209, 36601340, 19941162, 19499246, 18092194, 27062684, 28186987). ClinVar contains an entry for this variant (Variation ID: 55355). Based on the evidence outlined above, the variant was classified as pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 10, 2020	The c.5017_5019delCAC variant (also known as p.H1673del) is located in coding exon 15 of the BRCA1 gene. This variant results from an in-frame deletion of 3 nucleotides at positions 5017 to 5019. This results in the deletion of a histidine residue at codon 1673 that is not well conserved. This alteration has been reported in a German cohort of families with one or more cases of breast and at least one ovarian cancer (Meindl A et al, Int. J. Cancer 2002 Feb; 97(4):472-80). This alteration was also reported in 14 Northern Italian families with breast and/or ovarian cancer whose tumors demonstrated frequent BRCA1 loss-of-heterozygosity in tumors (Zuntini R et al. Oncotarget, 2017 Apr;8:22640-22648). This alteration segregates strongly with breast and ovarian cancer in multiple families (Ambry internal data; Zuntini R et al. Oncotarget, 2017 Apr;8:22640-22648). This alteration is also designated as 5136delCAC in the published literature. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Sep 01, 2021	This variant causes a deletion of histidine at codon 1673 in the BRCT1 domain of the BRCA1 protein. To our knowledge, functional studies have not been reported for this variant. In silico modeling has shown that His1673 in the BRCT domain of BRCA1 is predicted to interact with the BRCT domain of BARD1 (PMID 28186987). This variant has been reported in more than 20 unrelated individuals affected with breast and/or ovarian cancer (11802209, 19499246, 28186987, 28364669, 30725392, 33078592, 33801055, 33875706, 34063308), and a multifactorial analysis has reported a segregation likelihood ratio for pathogenicity of 17.5575 (PMID: 31131967). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Although additional studies are necessary to determine the mechanism of disease for this variant, this variant is classified as Likely Pathogenic based on the available clinical evidence. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs80358343; hg19: chr17-41219679;