rs80357318

Variant names:

• chr17-43091594-G-A
• rs80357318
• NM_007294.4:c.3937C>T

Your query was ambiguous. Multiple possible variants found:

• chr17-43091594-G-A
• chr17-43091594-G-C
• chr17-43091594-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.3937C>T​(p.Gln1313*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,872 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 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 stop_gained
• Clinical Significance: Pathogenic reviewed by expert panel P:16
• Conservation: PhyloP100: 0.675

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 17-43091594-G-A is Pathogenic according to our data. Variant chr17-43091594-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 37556.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43091594-G-A is described in Lovd as [Pathogenic]. Variant chr17-43091594-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.3937C>T	p.Gln1313*	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.3937C>T	p.Gln1313*	stop_gained	Exon 10 of 23	1	NM_007294.4	ENSP00000350283.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461872 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 727238

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:16

Revision: reviewed by expert panel

Submissions by phenotype

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

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. -

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

- -

May 29, 2002

Breast Cancer Information Core (BIC) (BRCA1)

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Oct 05, 2009

Sharing Clinical Reports Project (SCRP)

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 30, 2022

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary breast ovarian cancer syndrome Pathogenic:4

Sep 21, 2020

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.3937C>T (p.Gln1313X) 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 251230 control chromosomes (gnomAD). c.3937C>T has been reported in the literature in multiple individuals and families affected with Hereditary Breast And Ovarian Cancer Syndrome (e.g. Miki_1994, Lee_2011, Rummel_2013, Kang_2015, Rebbeck_2018). These data indicate that the variant is very likely to be associated with disease. Seven ClinVar submitters including an expert panel (ENIGMA) (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Dec 02, 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.Gln1313*) 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/or ovarian cancer (PMID: 7837387, 22010008, 25863477, 27153395). ClinVar contains an entry for this variant (Variation ID: 37556). RNA analysis performed to evaluate the impact of this premature translational stop signal on mRNA splicing indicates it does not significantly alter splicing (internal data). For these reasons, this variant has been classified as Pathogenic. -

Jan 31, 2014

Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Jun 24, 2021

St. Jude Molecular Pathology, St. Jude Children's Research Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The BRCA1 c.3937C>T (p.Gln1313Ter) change is a nonsense variant that is predicted to cause premature protein truncation and loss of normal protein function (PVS1). This variant is absent in gnomAD v2.1.1 (PM2_Supporting; https://gnomad.broadinstitute.org/). This variant is also absent in the FLOSSIES database which contains genetic variants from women older than 70 years of age who have never had cancer (https://whi.color.com/). This variant has been reported in multiple families with breast and ovarian cancer (PS4; PMID: 7837387, 27153395, 29339979, 29446198, 30322717). In summary, this variant meets criteria to be classified as pathogenic based on the ACMG/AMP criteria: PVS1, PS4, PM2_Supporting. -

not provided Pathogenic:3

Dec 06, 2023

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The BRCA1 c.3937C>T (p.Gln1313*) variant causes the premature termination of BRCA1 protein synthesis. This variant has been reported in the published literature in affected individuals with breast and/or ovarian cancer (PMIDs: 25863477 (2015), 27153395 (2016), 29339979 (2018), 30322717 (2018), 31742824 (2020), 32341426 (2020), and 34981296 (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 pathogenic. -

May 06, 2019

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 15, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nonsense 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 (PMID: 7837387, 21120943, 23192404, 22010008); 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 4056C>T; This variant is associated with the following publications: (PMID: 23192404, 25525159, 30678073, 31409081, 7837387, 16875939, 7545954, 25863477, 22010008, 12112659, 26994145, 21120943, 27783335, 27153395, 29339979, 31013702, 31432501, 32341426, 29446198, 31742824, 34981296, 28888541, 30322717) -

Hereditary cancer-predisposing syndrome Pathogenic:3

Mar 21, 2022

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 been reported in individuals and families affected with breast and/or ovarian cancer (PMID: 7545954, 16875939, 18284688, 21120943, 22010008, 23192404, 25863477, 27153395, 28503720, 32341426). This variant has been identified in 21 families among the CIMBA participants (PMID: 29446198) (https://cimba.ccge.medschl.cam.ac.uk/). 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. -

Aug 05, 2020

Sema4, Sema4

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Mar 17, 2022

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Q1313* pathogenic mutation (also known as c.3937C>T), located in coding exon 9 of the BRCA1 gene, results from a C to T substitution at nucleotide position 3937. This changes the amino acid from a glutamine to a stop codon within coding exon 9. This mutation has been identified in multiple families with breast and ovarian cancer (Shattuck-Eidens D et al. JAMA 1995 Feb;273:535-41; Caux-Moncoutier V et al. Hum. Mutat. 2011 Mar;32:325-34; Lecarpentier J et al. Breast Cancer Res. 2012 Jul;14(4):R99; Rummel SK et al. Breast Cancer Res. Treat. 2017 Aug;164(3):593-601; Heramb C et al. Hered. Cancer Clin. Pract. 2018 Jan;16:3; Rebbeck TR et al. Hum. Mutat. 2018 May;39:593-620). Of note, this alteration is also designated as 4056C>T 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. -

not specified Pathogenic:1

May 28, 2019

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The BRCA1 c.3937C>T; p.Gln1313Ter variant (rs80357318), also known as 4056C>T, is reported in the literature in multiple individuals and families affected with breast and ovarian cancer (Heramb 2018, Kang 2015, Lee 2011, Maxwell 2016, Miki 1994, Rebbeck 2018, Shattuck-Eidens 1995). This variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 37556), and is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. This variant induces an early termination codon and is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. References: Heramb C et al. BRCA1 and BRCA2 mutation spectrum - an update on mutation distribution in a large cancer genetics clinic in Norway. Hered Cancer Clin Pract. 2018 Jan 10;16:3. Kang E et al. The prevalence and spectrum of BRCA1 and BRCA2 mutations in Korean population: recent update of the Korean Hereditary Breast Cancer (KOHBRA) study. Breast Cancer Res Treat. 2015 May;151(1):157-68. Lee E et al. Characteristics of triple-negative breast cancer in patients with a BRCA1 mutation: results from a population-based study of young women. J Clin Oncol. 2011 Nov 20;29(33):4373-80. Maxwell KN et al. Evaluation of ACMG-Guideline-Based Variant Classification of Cancer Susceptibility and Non-Cancer-Associated Genes in Families Affected by Breast Cancer. Am J Hum Genet. 2016 May 5;98(5):801-817. Miki Y et al. A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1. Science. 1994 Oct 7;266(5182):66-71. Rebbeck TR et al. Mutational spectrum in a worldwide study of 29,700 families with BRCA1 or BRCA2 mutations. Hum Mutat. 2018 May;39(5):593-620. Shattuck-Eidens D et al. A collaborative survey of 80 mutations in the BRCA1 breast and ovarian cancer susceptibility gene. Implications for presymptomatic testing and screening. JAMA. 1995 Feb 15;273(7):535-41. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.29
CADD	Pathogenic	36
DANN	Uncertain	0.99
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Benign	0.13	N
Vest4		0.84
GERP RS		2.9

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: rs80357318; hg19: chr17-41243611;