rs80358347

Variant names:

• chr17-43057113-TCTC-T
• rs80358347
• NM_007294.4:c.5213_5215delGAG

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.5213_5215delGAG​(p.Gly1738del) variant causes a disruptive inframe deletion change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: BRCA1 NM_007294.4 disruptive_inframe_deletion
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6 U:1
• Conservation: PhyloP100: 4.68

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 mutagenesis_site Abolishes interaction with BRIP1. (size 0) in uniprot entity BRCA1_HUMAN there are 8 pathogenic changes around while only 0 benign (100%) 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 17-43057113-TCTC-T is Pathogenic according to our data. Variant chr17-43057113-TCTC-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 55463.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA1	NM_007294.4	c.5213_5215delGAG	p.Gly1738del	disruptive_inframe_deletion	Exon 19 of 23	ENST00000357654.9	NP_009225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9	c.5213_5215delGAG	p.Gly1738del	disruptive_inframe_deletion	Exon 19 of 23	1	NM_007294.4	ENSP00000350283.3

Frequencies

GnomAD3 genomes Cov.: 31

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

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Aug 24, 2023

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published in vitro functional studies demonstrate loss of transcriptional activity (Nepomuceno et al., 2022); Observed in an individual with a personal and family history consistent with pathogenic variants in this gene (Flaum et al., 2022); In-frame deletion of 1 amino acid in a non-repeat region; Not observed in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on protein structure/function; Also known as 5332_5334del; This variant is associated with the following publications: (PMID: 16267036, 15235020, 21203900, 19941162, 31131967, 18036263, 16280041, 17308087, 17924331, 24010542, 30209399, 15353005, 16489001, 17305420, 17902052, 17453335, 20516115, 23536787, 10220405, 24389207, 10196224, 9738006, 9811458, 9974970, 11301010, 31853058, 36169650, 36171434) -

Jul 27, 2023

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The BRCA1 c.5213_5215del (p.Gly1738del) variant has been reported in the published literature in individuals and families with hereditary breast and/or ovarian cancer (PMID: 16267036 (2005), 21203900 (2011), 36169650 (2022)). In addition, a transcriptional activation assay reported this variant has a damaging on protein function (PMID: 36171434 (2022)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Based on the available information, this variant is classified as likely pathogenic. -

Apr 15, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant results in the in-frame deletion of a glycine at codon 1738. It has been reported in two families with hereditary breast ovarian cancer (Konecny et al. 2011. PubMed ID: 21203900). In a functional study, this variant had greatly reduced transcription activity and lower protein expression compared to wildtype (Nepomuceno et al. 2022. PubMed ID: 36171434). Two missense alterations impacting this codon, p.G1738E and p.G1738R, have also been reported as likely pathogenic and pathogenic (Easton et al. 2007. PubMed ID: 17924331; Findlay et al. 2018. PubMed ID: 30209399). This variant has not been reported in a large population database, indicating this variant is rare. There are conflicting interpretations ranging from pathogenic to uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/55463/). This variant is interpreted as pathogenic. -

Hereditary breast ovarian cancer syndrome Pathogenic:2

Jun 27, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: BRCA1 c.5213_5215delGAG (p.Gly1738del) results in an in-frame deletion that is predicted to remove 1 amino acid from the encoded protein. The variant was absent in 251492 control chromosomes. c.5213_5215delGAG has been reported in the literature in multiple individuals affected with clinical features of Hereditary Breast And Ovarian Cancer Syndrome (example, Judkins_2005, Konecny_2011, NO_PMID), including 1 family reported internally. These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. A different variant affecting the same codon has been classified as pathogenic by our lab (c.5212G>A, p.Gly1738Arg), supporting the critical relevance of codon 1738 to BRCA1 protein function. At least one publication reports experimental evidence evaluating an impact on protein function. This variant was expressed in a HEK293FT cell line and showed a <1% transcriptional activity in a luciferase assay, correlating with a severe decrease in detectable BRCA1 protein (example, Nepomuceno_2022). The following publications have been ascertained in the context of this evaluation (PMID: 16267036, 21203900, 36171434, NO_PMID). ClinVar contains an entry for this variant (Variation ID: 55463). Based on the evidence outlined above, the variant was classified as pathogenic. -

Nov 11, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant, c.5213_5215del, results in the deletion of 1 amino acid(s) of the BRCA1 protein (p.Gly1738del), 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 hereditary breast and ovarian cancer (PMID: 21203900). ClinVar contains an entry for this variant (Variation ID: 55463). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. This variant disrupts a region of the BRCA1 protein in which other variant(s) (p.Gly1738Arg) have been determined to be pathogenic (PMID: 15353005, 16489001, 17305420, 17308087, 17453335, 17902052, 18036263, 20516115, 23536787, 24010542). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Jul 22, 2024

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.5213_5215delGAG variant (also known as p.G1738del) is located in coding exon 18 of the BRCA1 gene. This variant results from an in-frame GAG deletion at nucleotide positions 5213 to 5215. This results in the in-frame deletion of a glycine at codon 1738. This alteration has been identified in an individual diagnosed with ovarian cancer (Flaum N et al. Genet Med, 2022 Dec;24:2578-2586). This alteration has also been classified as likely deleterious based on a classification system using interspecific sequence variation (Abkevich V et al. J. Med. Genet., 2004 Jul;41:492-507). Two missense alterations impacting this codon, p.G1738E and p.G1738R, have also been reported as likely pathogenic and pathogenic, respectively (Easton D et al. Am J Hum Genet. 2007;81:873-883; Vallee M et al. Hum Mutat. 2012 Jan;33(1):22-8; Findlay, GM et al. Nature 2018 Oct;562(7726):217-222). A phenotype and family history weighing algorithm demonstrated this alteration is pathogenic (Personal communication). A transcriptional activation assay determined that this alteration results in impaired function (Nepomuceno TC et al. Sci Rep 2022 Sep;12(1):16203). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

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

May 29, 2002

Breast Cancer Information Core (BIC) (BRCA1)

Significance: Uncertain significance

Review Status: flagged submission

Collection Method: clinical testing

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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: rs80358347; hg19: chr17-41209130;