17-43094464-T-C

Position:

• chr17-43094464-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_007294.4(BRCA1):​c.1067A>G​(p.Gln356Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0551 in 1,614,048 control chromosomes in the GnomAD database, including 2,838 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.046 (213 hom., cov: 32)
  • Exomes 𝑓: 0.056 (2625 hom.)
• Consequence: BRCA1 NM_007294.4 missense
• Clinical Significance: Benign reviewed by expert panel U:2 B:42 O:1
• Conservation: PhyloP100: 2.37

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0026477277).
• BP6: Variant 17-43094464-T-C is Benign according to our data. Variant chr17-43094464-T-C is described in ClinVar as [Benign]. Clinvar id is 41803.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43094464-T-C is described in Lovd as [Benign]. Variant chr17-43094464-T-C is described in Lovd as [Pathogenic]. Variant chr17-43094464-T-C is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0639 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA1	NM_007294.4	c.1067A>G	p.Gln356Arg	missense_variant	10/23	ENST00000357654.9	NP_009225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9	c.1067A>G	p.Gln356Arg	missense_variant	10/23	1	NM_007294.4	ENSP00000350283.3

Frequencies

GnomAD3 genomes AF: 0.0456 AC: 6942 AN: 152212 Hom.: 212 Cov.: 32

Gnomad AFR AF: 0.0117

Gnomad AMI AF: 0.0164

Gnomad AMR AF: 0.0400

Gnomad ASJ AF: 0.0833

Gnomad EAS AF: 0.000576

Gnomad SAS AF: 0.0130

Gnomad FIN AF: 0.0843

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.0655

Gnomad OTH AF: 0.0545

GnomAD3 exomes AF: 0.0465 AC: 11681 AN: 251138 Hom.: 398 AF XY: 0.0471 AC XY: 6396 AN XY: 135736

Gnomad AFR exome AF: 0.00954

Gnomad AMR exome AF: 0.0264

Gnomad ASJ exome AF: 0.0761

Gnomad EAS exome AF: 0.000326

Gnomad SAS exome AF: 0.0132

Gnomad FIN exome AF: 0.0811

Gnomad NFE exome AF: 0.0648

Gnomad OTH exome AF: 0.0539

GnomAD4 exome AF: 0.0560 AC: 81929 AN: 1461718 Hom.: 2625 Cov.: 34 AF XY: 0.0554 AC XY: 40297 AN XY: 727152

Gnomad4 AFR exome AF: 0.00887

Gnomad4 AMR exome AF: 0.0273

Gnomad4 ASJ exome AF: 0.0779

Gnomad4 EAS exome AF: 0.000151

Gnomad4 SAS exome AF: 0.0136

Gnomad4 FIN exome AF: 0.0774

Gnomad4 NFE exome AF: 0.0627

Gnomad4 OTH exome AF: 0.0507

GnomAD4 genome AF: 0.0456 AC: 6943 AN: 152330 Hom.: 213 Cov.: 32 AF XY: 0.0453 AC XY: 3371 AN XY: 74492

Gnomad4 AFR AF: 0.0117

Gnomad4 AMR AF: 0.0399

Gnomad4 ASJ AF: 0.0833

Gnomad4 EAS AF: 0.000578

Gnomad4 SAS AF: 0.0128

Gnomad4 FIN AF: 0.0843

Gnomad4 NFE AF: 0.0655

Gnomad4 OTH AF: 0.0539

Alfa AF: 0.0625 Hom.: 743

Bravo AF: 0.0413

TwinsUK AF: 0.0596 AC: 221

ALSPAC AF: 0.0537 AC: 207

ESP6500AA AF: 0.0102 AC: 45

ESP6500EA AF: 0.0642 AC: 552

ExAC AF: 0.0441 AC: 5350

Asia WGS AF: 0.00577 AC: 20 AN: 3478

EpiCase AF: 0.0725

EpiControl AF: 0.0693

ClinVar

Significance: Benign

Submissions summary: Uncertain:2 Benign:42 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

not specified Benign:14 Other:1

Benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	research	Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	Jan 31, 2014	- -
Benign, criteria provided, single submitter	clinical testing	GeneKor MSA	Nov 01, 2017	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -
Benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The p.Gln356Arg variant is not expected to have clinical significance because it is identified at a high frequency in various different populations of origin. In the 1000 genomes and exome variant server databases it was identified in 658 of 22636 control chromosomes. In addition, this variant was identified in the UMD database 16 x and 3 times in the presence of a co-occuring pathogenic variant increasing the likelihood this variant does not have clinical significance. In summary, based on the above information, this variant is classified as benign. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 23, 2016	p.Gln356Arg in exon 10 of BRCA1: This variant is not expected to have clinical s ignificance because it has been identified in 7.83% (518/6614) of Finnish chromo somes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs1799950). -
Benign, criteria provided, single submitter	clinical testing	Cancer Genetics and Genomics Laboratory, British Columbia Cancer Agency	Apr 18, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 15, 2016	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 13, 2013	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Breast-ovarian cancer, familial, susceptibility to, 1 Uncertain:1 Benign:11

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jan 01, 2019	- -
Likely benign, no assertion criteria provided	literature only	Pathway Genomics	Jul 24, 2014	- -
Benign, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Feb 05, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Mar 15, 2011	- -
Benign, criteria provided, single submitter	literature only	Counsyl	Jan 02, 2014	High frequency in a 1kG or ESP population: 6.4 %. -
Benign, criteria provided, single submitter	clinical testing	Michigan Medical Genetics Laboratories, University of Michigan	Nov 03, 2014	- -
Benign, reviewed by expert panel	curation	Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	Aug 10, 2015	IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 1 based on posterior probability = 0.00000000000204. Also class 1 based on frequency >1% in an outbred sampleset. Frequency 0.05409 (European), derived from 1000 genomes (2012-04-30). -
Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Genomic Research Center, Shahid Beheshti University of Medical Sciences	May 03, 2020	- -
Uncertain significance, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA1)	Dec 22, 1999	- -

Hereditary cancer-predisposing syndrome Benign:5

Benign, criteria provided, single submitter	clinical testing	Vantari Genetics	Nov 27, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Nov 05, 2014	- -
Benign, criteria provided, single submitter	curation	Sema4, Sema4	Jan 29, 2020	- -
Benign, no assertion criteria provided	clinical testing	True Health Diagnostics	Mar 02, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 18, 2014	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Hereditary breast ovarian cancer syndrome Benign:5

Benign, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Apr 17, 2015	- -
Benign, criteria provided, single submitter	clinical testing	National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	Apr 19, 2022	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 07, 2014	- -
Benign, criteria provided, single submitter	research	Genetics Program, Instituto Nacional de Cancer	Nov 01, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Dec 06, 2016	- -
Benign, no assertion criteria provided	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jul 13, 2012	- -

Breast ductal adenocarcinoma Uncertain:1

Uncertain significance, no assertion criteria provided

research

Next Generation Diagnostics, Novartis Institutes for BioMedical Research, Inc.

Jul 20, 2015

- -

Familial cancer of breast;C2676676:Breast-ovarian cancer, familial, susceptibility to, 1;C3280442:Pancreatic cancer, susceptibility to, 4;C4554406:Fanconi anemia, complementation group S Benign:1

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Mar 23, 2022

- -

Malignant tumor of breast Benign:1

Benign, no assertion criteria provided

clinical testing

Center of Medical Genetics and Primary Health Care

-

- -

Familial cancer of breast Benign:1

Benign, criteria provided, single submitter

clinical testing

Baylor Genetics

Feb 23, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Uncertain	0.050
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.54	D;.;.;.;T;T;.;.;T
Eigen	Benign	0.025
Eigen_PC	Benign	-0.12
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.66	T;T;T;T;T;T;T;T;T
MetaRNN	Benign	0.0026	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.85	T
MutationAssessor	Pathogenic	3.4	M;M;.;.;.;.;.;.;.
PrimateAI	Benign	0.27	T
PROVEAN	Uncertain	-3.3	D;D;D;D;.;D;D;D;D
REVEL	Uncertain	0.42
Sift	Uncertain	0.014	D;D;D;D;.;D;D;D;D
Sift4G	Uncertain	0.018	D;D;D;D;.;T;.;D;T
Polyphen		1.0	D;.;.;D;.;.;.;.;.
Vest4		0.36
MPC		0.43
ClinPred		0.033	T
GERP RS		3.7
Varity_R		0.12
gMVP		0.043

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: rs1799950; hg19: chr17-41246481; COSMIC: COSV58788306; COSMIC: COSV58788306;