rs80357215

Variant names:

• chr17-43094465-G-A
• rs80357215
• NM_007294.4:c.1066C>T

Your query was ambiguous. Multiple possible variants found:

• chr17-43094465-G-A
• chr17-43094465-G-C
• chr17-43094465-G-T

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.1066C>T​(p.Gln356*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,702 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: 6.8e-7 (0 hom.)
• Consequence: BRCA1 NM_007294.4 stop_gained
• Clinical Significance: Pathogenic reviewed by expert panel P:18
• Conservation: PhyloP100: 1.43

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 17-43094465-G-A is Pathogenic according to our data. Variant chr17-43094465-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 54114.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43094465-G-A is described in Lovd as [Pathogenic]. Variant chr17-43094465-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA1	NM_007294.4	c.1066C>T	p.Gln356*	stop_gained	Exon 10 of 23	ENST00000357654.9	NP_009225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9	c.1066C>T	p.Gln356*	stop_gained	Exon 10 of 23	1	NM_007294.4	ENSP00000350283.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461702 Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1 AN XY: 727150

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:18

Revision: reviewed by expert panel

Submissions by phenotype

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

Sep 08, 2016

Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

Variant allele predicted to encode a truncated non-functional protein. -

Jan 01, 2017

Genologica Medica

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

- -

Oct 28, 2021

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 02, 2020

BRCAlab, Lund University

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Oct 05, 2007

Breast Cancer Information Core (BIC) (BRCA1)

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Dec 18, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 05, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

A pathogenic variant was detected in this sample . This variant changes 1 nucleotide in exon 10 of the BRCA1 gene, c.1066C>T (p.Gln356X) 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. his variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Also it has been reported in the literature in multiple individuals affected with breast and ovarian cancer (PMID: 30199306 , 30606148 , 29884136 ,16683254). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Twelve ClinVar submissions from clinical diagnostic laboratories and an expert panel (ENIGMA)(evaluation after 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. This variant confirmed by Sanger sequencing . -

not provided Pathogenic:3

Sep 18, 2015

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This pathogenic variant is denoted BRCA1 c.1066C>T at the cDNA level and p.Gln356Ter (Q356X) at the protein level. Using alternate nomenclature, this variant would also be defined as BRCA1 1185C>T. The substitution creates a nonsense variant, which changes a Glutamine to a premature stop codon (CAG>TAG), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant has been reported in at least four breast and/or ovarian cancer families (van der Hout 2006, Tang 1999) and is considered pathogenic. -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Pathogenic:3

Jan 15, 2020

Color Diagnostics, LLC DBA Color Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant changes 1 nucleotide in exon 10 of the BRCA1 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. 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 (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. -

Nov 01, 2022

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Q356* pathogenic mutation (also known as c.1066C>T), located in coding exon 9 of the BRCA1 gene, results from a C to T substitution at nucleotide position 1066. This changes the amino acid from a glutamine to a stop codon within coding exon 9. This mutation has been previously reported in several hereditary breast and ovarian cancer (HBOC) syndrome families (Tang NL et al. J. Natl. Cancer Inst. 1999 May;91:882-5; van der Hout AH et al. Hum. Mutat. 2006 Jul;27:654-66; Cotrim DP et al. BMC Cancer 2019 Jan;19:4; Siraj AK et al. Hum. Mutat. 2019 Mar; Abulkhair O et al. J Glob Oncol. 2018 Aug;4:1-9; Bhaskaran SP et al. Int. J. Cancer, 2019 Jan). This alteration was also identified in a large, worldwide study of BRCA1/2 mutation positive families (Rebbeck TR et al. Hum. Mutat. 2018 05;39:593-620). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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. -

Feb 05, 2025

Molecular Diagnostics Laboratory, Catalan Institute of Oncology

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PVS1, PM5_PTC_Strong, PM2_Suppoting c.1066C>T, located in exon 10 (11 according BIC nomenclature) of the BRCA1 gene, is a nonsense variant expected to result in loss of function by premature protein truncation and nonsense-mediated mRNA decay, p.(Gln356*)(PVS1, PM5_PTC_Strong).It is not present in the population database gnomAD v2.1.1, non cancer dataset (PM2_Supporting). No effect is predicted on splicing by SpliceAI. To our knowledge, functional studies have not been reported for this variant. In addition, the variant was also identified in the following databases: BRCA Exchange (Pathogenic: Variant allele predicted to encode a truncated non-functional protein), ClinVar (16x Pathogenic) and LOVD (1x uncertain significance, 18x pathogenic). Based on the currently available information, c.1066C>T is classified as a pathogenic variant according to ClinGen-BRCA1 Guidelines version v1.0.0. -

Hereditary breast ovarian cancer syndrome Pathogenic:3

Apr 19, 2023

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.Gln356*) 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 breast and ovarian cancer (PMID: 16683254, 30199306, 30606148). ClinVar contains an entry for this variant (Variation ID: 54114). For these reasons, this variant has been classified as Pathogenic. -

May 14, 2019

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.1066C>T (p.Gln356X) 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. The variant was absent in 251086 control chromosomes (gnomAD) but has been reported in the literature in multiple individuals affected with breast and ovarian cancer (e.g. Abulkhair _2018, Cotrim_2019, van der Hout_2006, Pajares_2018). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six ClinVar submissions from clinical diagnostic laboratories and an expert panel (ENIGMA)(evaluation after 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Nov 03, 2022

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Gln356X variant in BRCA1 has been reported in at least 8 individuals affected with breast and/or ovarian cancer (selected references: Abulkhair 2018 PMID: 30199306, Cotrim 2019 PMID: 30606148, van der Hout 2006 PMID: 16683254, Pajares 2018 PMID: 29884136, Siraj 2019 PMID: 30825404, Gao 2020 PMID: 31825140) and it was classified as pathogenic on Sep 08, 2016 by the ClinGen-approved Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) expert panel (Variation ID 54114). It was absent from large population studies. This nonsense variant leads to a premature termination codon at position 356, which is predicted to lead to a truncated or absent protein. Loss of function of the BRCA1 gene is an established disease mechanism in autosomal dominant hereditary breast and ovarian cancer syndrome. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant hereditary breast and ovarian cancer syndrome. ACMG/AMP Criteria applied: PVS1, PS4_Moderate, PM2_Supporting. -

Familial cancer of breast Pathogenic:1

Nov 16, 2018

Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.071	D
BayesDel_noAF	Benign	-0.14
CADD	Pathogenic	31
DANN	Benign	0.97
Eigen	Uncertain	0.31
Eigen_PC	Benign	0.0057
FATHMM_MKL	Benign	0.76	D
Vest4		0.84
GERP RS		2.7

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: rs80357215; hg19: chr17-41246482;