NM_007294.4:c.791_794delGTTC

Variant names:

• chr17-43094736-AGAAC-A
• rs80357707
• NM_007294.4:c.791_794delGTTC

Variant summary

Our verdict is Pathogenic. The variant received 19 ACMG points: 19P and 0B. PVS1 PM2 PP3 PP5_Very_Strong

The NM_007294.4(BRCA1):​c.791_794delGTTC​(p.Ser264MetfsTer33) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,458,418 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: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: BRCA1 NM_007294.4 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:12
• Conservation: PhyloP100: 2.27
• Publications: 15 publications found

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 Gene-Disease associations (from GenCC):

• breast-ovarian cancer, familial, susceptibility to, 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• Fanconi anemia, complementation group S

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics
• pancreatic cancer, susceptibility to, 4

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• hereditary breast ovarian cancer syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Fanconi anemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 19 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
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 17-43094736-AGAAC-A is Pathogenic according to our data. Variant chr17-43094736-AGAAC-A is described in ClinVar as Pathogenic. ClinVar VariationId is 55705.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_007294.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BRCA1	NM_007294.4	MANE Select	c.791_794delGTTC	p.Ser264MetfsTer33	frameshift	Exon 10 of 23	NP_009225.1
	BRCA1	NM_001407581.1		c.791_794delGTTC	p.Ser264MetfsTer33	frameshift	Exon 10 of 24	NP_001394510.1
	BRCA1	NM_001407582.1		c.791_794delGTTC	p.Ser264MetfsTer33	frameshift	Exon 10 of 24	NP_001394511.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BRCA1	ENST00000357654.9	TSL:1 MANE Select	c.791_794delGTTC	p.Ser264MetfsTer33	frameshift	Exon 10 of 23	ENSP00000350283.3
	BRCA1	ENST00000471181.7	TSL:1	c.791_794delGTTC	p.Ser264MetfsTer33	frameshift	Exon 10 of 24	ENSP00000418960.2
	BRCA1	ENST00000470026.6	TSL:1	c.791_794delGTTC	p.Ser264MetfsTer33	frameshift	Exon 10 of 23	ENSP00000419274.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000801 AC: 2 AN: 249662 AF XY: 0.0000148

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000292

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000885

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1458418 Hom.: 0 AF XY: 0.00000276 AC XY: 2 AN XY: 725076

African (AFR) AF: 0.00 AC: 0 AN: 33284

American (AMR) AF: 0.0000226 AC: 1 AN: 44330

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26012

East Asian (EAS) AF: 0.00 AC: 0 AN: 39656

South Asian (SAS) AF: 0.00 AC: 0 AN: 86026

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53320

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5750

European-Non Finnish (NFE) AF: 9.01e-7 AC: 1 AN: 1109808

Other (OTH) AF: 0.00 AC: 0 AN: 60232

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:5

Aug 18, 2017

Counsyl

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com.

May 24, 2021

Molecular Oncology, Hospital Universitario Central de Asturias (HUCA)

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: case-control

Oct 02, 2015

Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Dec 30, 1999

Breast Cancer Information Core (BIC) (BRCA1)

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Nov 10, 2023

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Hereditary breast ovarian cancer syndrome Pathogenic:3

Oct 28, 2022

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.791_794delGTTC (p.Ser264MetfsX33) 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 8e-06 in 249662 control chromosomes. c.791_794delGTTC has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (examples: Rebbeck_2018, Maistro_2016). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six 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.

Nov 01, 2021

Genetics Program, Instituto Nacional de Cancer

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

Oct 21, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Ser264Metfs*33) 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 (rs80357707, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with breast and/or ovarian cancer (PMID: 11857748, 12955716, 23683081, 27425403, 27914478, 29907814). This variant is also known as 910delGTTC, 910del4, and 910_913delGTTC. ClinVar contains an entry for this variant (Variation ID: 55705). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic.

not provided Pathogenic:2

Aug 02, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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; 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 910delGTTC; Observed in individuals with a personal or family history including breast and ovarian cancer (Llort et al., 2002; Alemar et al., 2016; Maistro et al., 2016); This variant is associated with the following publications: (PMID: 27425403, 11857748, 27914478, 29907814, 29161300, 30720243, 31447099)

Nov 09, 2020

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This frameshift variant causes the premature termination of BRCA1 protein synthesis. In addition, it has been reported in individuals with breast cancer and ovarian cancer in the published literature (PMID: 29161300 (2017), 27914478 (2016), 23683081 (2013), 12955716 (2003)). Based on the available information, this variant is classified as pathogenic.

Hereditary cancer-predisposing syndrome Pathogenic:2

Feb 26, 2021

Color Diagnostics, LLC DBA Color Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant deletes 4 nucleotides 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. To our knowledge, functional studies have not been reported for this variant. This variant has been detected in four hereditary breast and ovarian cancer families (PMID: 11857748, 12014998, 23683081, 27425403, 27914478) in which this variant was confirmed present in at least one individual affected with early-onset breast cancer and two individuals affected with ovarian cancer (PMID: 12014998, 27914478). This variant has been identified in 2/249662 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.

Jul 16, 2025

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.791_794delGTTC pathogenic mutation, located in coding exon 9 of the BRCA1 gene, results from a deletion of 4 nucleotides at nucleotide positions 791 to 794, causing a translational frameshift with a predicted alternate stop codon (p.S264Mfs*33). This alteration has been reported in multiple Spanish and Brazilian HBOC families (Llort G et al. Hum. Mutat. 2002 Mar;19(3):307; Díez O et al. Hum. Mutat. 2003 Oct;22:301-12; Blay P et al. BMC Cancer 2013 May;13:243; Alemar B et al. Cancer Genet. 2016 09;209:417-422; Alemar B et al. PLoS ONE 2017 Nov;12:e0187630; Palmero EI et al. Sci. Rep. 2018 Jun;8:9188). This variant has also been identified in conjunction with another BRCA1 pathogenic variant in a 14 year old female with ovarian insufficiency who was suspected to have Fanconi anemia based on chromosomal breakage studies, although she did not report other clinical features of Fanconi anemia, and the phase of the two variants was not able to be confirmed by familial testing (Helbling-Leclerc A et al. Int J Mol Sci. 2024 Nov;25(22)). Of note, in silico splice site analysis predicts that this alteration will result in the creation or strengthening of a novel splice donor site. RNA studies have demonstrated that this alteration results in an increase in a naturally occurring transcript predicted to lead to a protein with an in-frame deletion of 1103 amino acids (Helbling-Leclerc A et al. Int J Mol Sci. 2024 Nov;25(22); Ambry internal data). This transcript is known as Δ11q in the literature, and functional studies are discordant with regard to retained activity and the clinical impact of loss of these amino acids (Colombo M et al. Hum. Mol. Genet. 2014; 23(14):3666–3680; Thakur S et al. Mol. Cell. Biol. 1997 Jan; 17(1):444-52; Huber LJ et al. Mol. Cell. Biol. 2001 Jun; 21(12):4005-15). Based on the majority of available evidence to date, this variant is likely to be pathogenic. However, carriers of this variant and their families may present with reduced risks, and not with the typical clinical characteristics of a high-risk pathogenic BRCA1 alteration. As risk estimates are unknown at this time, clinical correlation is advised.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.3
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.66		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.66		Position offset: 8

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs80357707; hg19: chr17-41246753;