17-43047679-G-A

Variant names:

• chr17-43047679-G-A
• rs397509283
• NM_007294.4:c.5431C>T

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_007294.4(BRCA1):​c.5431C>T​(p.Gln1811*) 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 1,461,876 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★★). Synonymous variant affecting the same amino acid position (i.e. Q1811Q) has been classified as Uncertain significance.

• 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: 2.73
• Publications: 20 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 18 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 146 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-43047679-G-A is Pathogenic according to our data. Variant chr17-43047679-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 55577.Status of the report is reviewed_by_expert_panel, 3 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.5431C>T	p.Gln1811*	stop_gained	Exon 22 of 23	NP_009225.1
	BRCA1	NM_001407581.1		c.5497C>T	p.Gln1833*	stop_gained	Exon 23 of 24	NP_001394510.1
	BRCA1	NM_001407582.1		c.5497C>T	p.Gln1833*	stop_gained	Exon 23 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.5431C>T	p.Gln1811*	stop_gained	Exon 22 of 23	ENSP00000350283.3
	BRCA1	ENST00000471181.7	TSL:1	c.5494C>T	p.Gln1832*	stop_gained	Exon 23 of 24	ENSP00000418960.2
	BRCA1	ENST00000470026.6	TSL:1	c.5431C>T	p.Gln1811*	stop_gained	Exon 22 of 23	ENSP00000419274.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461876 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727242

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1112002

Other (OTH) AF: 0.00 AC: 0 AN: 60396

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:18

Revision: reviewed by expert panel

Submissions by phenotype

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

Oct 18, 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

Sep 25, 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.

Oct 10, 2015

Quest Diagnostics Nichols Institute San Juan Capistrano

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 BRCA1 gene. This pathogenic mutation (also known as c.5494C>T), located in coding exon 23 of the BRCA1 gene, results from a C to T substitution at nucleotide position 5494. This changes the amino acid from a glutamine to a stop codon within coding exon 23 . 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. his mutation has been reported in multiple individuals with hereditary breast and/or ovarian cancer (PMID: 11773283, 22434525, 10644434, 24010542, 26300996, 25452441, 16944269, 29752822, 30209399, 29446198, 30825404, 31209999, 29297111, 29805665, 30352249, 31825140). Multiple ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as "pathogenic." Based on the evidence outlined above, the variant was classified as pathogenic. This variant was confirmed by Sanger sequencing .

Mar 10, 2022

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

May 08, 2023

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Criteria applied: PVS1_STR,PS4,PM2_SUP

Mar 02, 2020

BRCAlab, Lund University

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

not provided Pathogenic:4

Dec 19, 2019

Clinical Genetics and Genomics, Karolinska University Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nov 13, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nonsense variant predicted to result in protein truncation in a gene for which loss-of-function is a known mechanism of disease; Not observed 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 5550C>T; This variant is associated with the following publications: (PMID: 11773283, 22434525, 10644434, 24010542, 26300996, 25452441, 16944269, 29752822, 30209399, 29446198, 30825404, 31209999, 29297111, 29805665, 30352249, 31825140, 32438681, 34645131)

Jan 01, 2020

GeneKor MSA

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This is a single base substitution, replacing the Glutamine at position 1811 of the BRCA1 protein by a Termination codon. It is expected to result in a truncated, non-functional protein. Truncating variants in BRCA1 are known to be pathogenic.

Nov 03, 2021

Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Hereditary breast ovarian cancer syndrome Pathogenic:2

Dec 12, 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.Gln1811*) in the BRCA1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 53 amino acid(s) of the BRCA1 protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with hereditary breast and/or ovarian cancer (PMID: 10644434, 22434525, 24010542, 25452441, 29446198, 29752822). This variant is also known as c.5550C>T. ClinVar contains an entry for this variant (Variation ID: 55577). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant disrupts a region of the BRCA1 protein in which other variant(s) (p.Arg1835*, p.Trp1815*) have been determined to be pathogenic (PMID: 8554067, 8968102, 11739404, 12360400, 20104584, 26187060, 27553291). 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.

Apr 30, 2018

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.5431C>T (p.Gln1811X) 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 (eg. c.5444G>A/p.Trp1815*, c.5470_5477delATTGGGCA). The variant was absent in 246268 control chromosomes (gnomAD). The variant, c.5431C>T, has been reported in the literature in multiple individuals affected with Hereditary Breast and Ovarian Cancer (Couch_2015, Fostira_2012, Siraj_2017). 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. Multiple ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as "pathogenic." Based on the evidence outlined above, the variant was classified as pathogenic.

Malignant tumor of urinary bladder Pathogenic:1

Laboratory of Urology, Hospital Clinic de Barcelona

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

Pancreatic cancer, susceptibility to, 4 Pathogenic:1

Oct 11, 2024

Department of Human Genetics, Hannover Medical School

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PVS1, PM2_Supporting, PM5_Strong

Hereditary cancer-predisposing syndrome Pathogenic:1

Nov 02, 2022

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Q1811* pathogenic mutation (also known as c.5431C>T), located in coding exon 21 of the BRCA1 gene, results from a C to T substitution at nucleotide position 5431. This changes the amino acid from a glutamine to a stop codon within coding exon 21. This mutation has been reported in multiple individuals with hereditary breast and/or ovarian cancer (Wagner T et al. Genomics, 1999 Dec;62:369-76; Findlay GM et al. Nature, 2018 10;562:217-222; Li JY et al. Int. J. Cancer, 2019 01;144:281-289; Rebbeck TR et al. Hum. Mutat., 2018 05;39:593-620; Wei H et al. Oncol Lett, 2018 Jun;15:9420-9428; Kotoula V et al. Am J Cancer Res, 2017 Jan;7:98-114; Alhuqail AJ et al. Breast Cancer Res. Treat., 2018 Apr;168:695-702; Laitman Y et al. Hum. Mutat., 2019 Jun). 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.

Familial cancer of breast Pathogenic:1

Nov 19, 2024

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Criteria applied: PVS1,PM5_STR,PM2_SUP

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.11
CADD	Pathogenic	39
DANN	Uncertain	0.99
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.50	T
MetaRNN	Benign	0.37	T
MetaSVM	Benign	-0.37	T
PhyloP100		2.7
PROVEAN	Benign	-0.35	N
REVEL	Uncertain	0.39
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Vest4		0.45
MutPred		0.28		Gain of sheet (P = 0.0344)
MVP		0.86
ClinPred		0.86	D
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
SpliceAI score (max)		0.41		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.41		Position offset: 24

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

Other links and lift over

dbSNP: rs397509283; hg19: chr17-41199696;