17-43092113-T-C

Variant names:

• chr17-43092113-T-C
• rs2227945
• NM_007294.4:c.3418A>G

Variant summary

Our verdict is Benign. The variant received -24 ACMG points: 0P and 24B. BA1 BP5_Strong BP1_Strong BS3 BS2

This summary comes from the ClinGen Evidence Repository: The c.3418A>G variant in BRCA1 is a missense variant predicted to cause substitution of Serine by Glycine at amino acid 1140 (p.Ser1140Gly). The highest non-cancer, non-founder population filter allele frequency in gnomAD v2.1 (exomes only, non-cancer subset, read depth ≥20) or gnomAD v3.1 (non-cancer subset, read depth ≥20) is 0.03171 in the African/African-American population, which is above the ENIGMA BRCA1/2 VCEP threshold (>0.001) for BA1 (BA1 met). This missense variant is located outside of a key functional domain and was not predicted to alter mRNA splicing using the SpliceAI predictor (score 0.06, score threshold <0.1) (BP1_Strong met). Reported by one calibrated study to exhibit protein function similar to benign control variants (PMID:32546644) (BS3 met). This variant has been observed in more than 10 individuals with features considered inconsistent with an FA-associated phenotype, and (Likely) Pathogenic variant seen in trans or variant is homozygous (total score 4 points) (BS2 met; Invitae internal contributor). Multifactorial likelihood ratio analysis using clinically calibrated data produced a combined LR for this variant of 0.00029 (based on Co-occurrence LR=0.00029), below the threshold for Very strong benign evidence (LR <0.00285) (BP5_Very strong met; PMID:16014699). In summary, this variant meets the criteria to be classified as a Benign variant for BRCA1-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (BA1, BP1_Strong, BS3, BS2, BP5_Very strong). LINK:https://erepo.genome.network/evrepo/ui/classification/CA002212/MONDO:0011450/092

• Frequency:
  • Genomes: 𝑓 0.0097 (34 hom., cov: 32)
  • Exomes 𝑓: 0.0010 (21 hom.)
• Consequence: BRCA1 NM_007294.4 missense
• Clinical Significance: Benign reviewed by expert panel U:1 B:32 O:1
• Conservation: PhyloP100: 0.301
• Publications: 49 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: Benign. The variant received -24 ACMG points.

• BP1: For more information check the summary or visit ClinGen Evidence Repository.
• BP5: For more information check the summary or visit ClinGen Evidence Repository.
• BS2: For more information check the summary or visit ClinGen Evidence Repository.
• BS3: For more information check the summary or visit ClinGen Evidence Repository.
• BA1: For more information check the summary or visit ClinGen Evidence Repository.

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.3418A>G	p.Ser1140Gly	missense	Exon 10 of 23	NP_009225.1
	BRCA1	NM_001407581.1		c.3418A>G	p.Ser1140Gly	missense	Exon 10 of 24	NP_001394510.1
	BRCA1	NM_001407582.1		c.3418A>G	p.Ser1140Gly	missense	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.3418A>G	p.Ser1140Gly	missense	Exon 10 of 23	ENSP00000350283.3
	BRCA1	ENST00000471181.7	TSL:1	c.3418A>G	p.Ser1140Gly	missense	Exon 10 of 24	ENSP00000418960.2
	BRCA1	ENST00000470026.6	TSL:1	c.3418A>G	p.Ser1140Gly	missense	Exon 10 of 23	ENSP00000419274.2

Frequencies

GnomAD3 genomes AF: 0.00970 AC: 1476 AN: 152222 Hom.: 34 Cov.: 32

Gnomad AFR AF: 0.0341

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00236

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.00669

GnomAD2 exomes AF: 0.00252 AC: 633 AN: 251092 AF XY: 0.00166

Gnomad AFR exome AF: 0.0335

Gnomad AMR exome AF: 0.00191

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000141

Gnomad OTH exome AF: 0.000980

GnomAD4 exome AF: 0.00105 AC: 1532 AN: 1461540 Hom.: 21 Cov.: 38 AF XY: 0.000873 AC XY: 635 AN XY: 727082

African (AFR) AF: 0.0350 AC: 1172 AN: 33478

American (AMR) AF: 0.00192 AC: 86 AN: 44724

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.0000696 AC: 6 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53230

Middle Eastern (MID) AF: 0.00121 AC: 7 AN: 5768

European-Non Finnish (NFE) AF: 0.000117 AC: 130 AN: 1111862

Other (OTH) AF: 0.00217 AC: 131 AN: 60392

GnomAD4 genome AF: 0.00972 AC: 1481 AN: 152340 Hom.: 34 Cov.: 32 AF XY: 0.00906 AC XY: 675 AN XY: 74506

African (AFR) AF: 0.0341 AC: 1419 AN: 41564

American (AMR) AF: 0.00235 AC: 36 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10632

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000162 AC: 11 AN: 68030

Other (OTH) AF: 0.00662 AC: 14 AN: 2116

Alfa AF: 0.00375 Hom.: 22

Bravo AF: 0.0105

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.0309 AC: 136

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00311 AC: 377

Asia WGS AF: 0.00318 AC: 11 AN: 3478

EpiCase AF: 0.000273

EpiControl AF: 0.000296

ClinVar

Significance: Benign

Submissions summary: Uncertain:1 Benign:32 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1 Uncertain:1 Benign:7

Mar 02, 2020

BRCAlab, Lund University

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jan 02, 2014

Counsyl

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: literature only

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.

Feb 22, 2018

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.

May 01, 2016

Department of Medical Genetics, University Hospital of North Norway

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Sep 21, 2015

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nov 03, 2014

Michigan Medical Genetics Laboratories, University of Michigan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

May 29, 2002

Breast Cancer Information Core (BIC) (BRCA1)

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

not specified Benign:7 Other:1

May 05, 2017

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Sep 19, 2013

ITMI

Significance: not provided

Review Status: no classification provided

Collection Method: reference population

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

The BRCA1, c.3418A>G, p.Ser1140Gly variant has been reported in the literature in at least 18/44788 proband chromosomes of individuals with sporadic as well as high-risk breast and /or ovarian cancer. It has also been found in 4/5118 control chromosomes evaluated (Tavtigian_2006_16014699, Abkevich_2004_15235020, Johnson_2007_17341484, McKean-Cowdin_2005_15726418, Alsop_2012_22711857, Elstrodt_2006_16397213, Tazzite_2012_22425665, Velasco_2005_15937982, Soegaard_2008_18559594). It is listed in the dbSNP database (ID#: rs2227945) as coming from a clinical source with a minor allele frequency of 0.011, having been observed in 25 chromosomes (1000 genomes), increasing the likelihood that this is benign variant. It has been listed in the UMD (x14 as neutral), BIC (x29 as UV) and the CNPHI (ACMG 3) databases. In addition, in the UMD mutation database, the variant was observed to co-occur with pathogenic BRCA1 [c.2890G>T (p.Gly964X) and c.415C>T (p.Gln139X)] as well as BRCA2 [c.2092delC (p.Leu698TyrfsX32)] variants, increasing the likelihood that p.Ser1140Gly is benign. This residue is not conserved in mammals and the variant amino acid Glycine (Gly) is present in the mouse. Computational analyses (PolyPhen, SIFT, AlignGVGD) does not predict any effect on the protein function, increasing the likelihood this variant does not have functional significance. In summary, based on the above information, this variant is classified as Benign.

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Mar 03, 2014

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

not provided Benign:5

Jul 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BRCA1: BP4, BS1, BS2

Oct 14, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Jul 13, 2012

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: research

Oct 09, 2017

Mayo Clinic Laboratories, Mayo Clinic

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Hereditary breast ovarian cancer syndrome Benign:5

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Oct 15, 2013

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Feb 14, 2017

Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nov 01, 2021

Genetics Program, Instituto Nacional de Cancer

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: research

Apr 19, 2022

National Health Laboratory Service, Universitas Academic Hospital and University of the Free State

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Hereditary cancer-predisposing syndrome Benign:4

Nov 18, 2014

Color Diagnostics, LLC DBA Color Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jan 03, 2018

True Health Diagnostics

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Nov 18, 2014

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Mar 26, 2020

Sema4, Sema4

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: curation

Breast and/or ovarian cancer Benign:1

Jul 06, 2021

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BRCA1-related cancer predisposition Benign:1

Jun 11, 2024

ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen

Significance: Benign

Review Status: reviewed by expert panel

Collection Method: curation

The c.3418A>G variant in BRCA1 is a missense variant predicted to cause substitution of Serine by Glycine at amino acid 1140 (p.Ser1140Gly). The highest non-cancer, non-founder population filter allele frequency in gnomAD v2.1 (exomes only, non-cancer subset, read depth >=20) or gnomAD v3.1 (non-cancer subset, read depth >=20) is 0.03171 in the African/African-American population, which is above the ENIGMA BRCA1/2 VCEP threshold (>0.001) for BA1 (BA1 met). This missense variant is located outside of a key functional domain and was not predicted to alter mRNA splicing using the SpliceAI predictor (score 0.06, score threshold <0.1) (BP1_Strong met). Reported by one calibrated study to exhibit protein function similar to benign control variants (PMID: 32546644) (BS3 met). This variant has been observed in more than 10 individuals with features considered inconsistent with an FA-associated phenotype, and (Likely) Pathogenic variant seen in trans or variant is homozygous (total score 4 points) (BS2 met; Invitae internal contributor). Multifactorial likelihood ratio analysis using clinically calibrated data produced a combined LR for this variant of 0.00029 (based on Co-occurrence LR=0.00029), below the threshold for Very strong benign evidence (LR <0.00285) (BP5_Very strong met; PMID: 16014699). In summary, this variant meets the criteria to be classified as a Benign variant for BRCA1-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (BA1, BP1_Strong, BS3, BS2, BP5_Very strong).

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

Oct 21, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Familial cancer of breast Benign:1

Sep 25, 2018

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was classified as: Benign. The following ACMG criteria were applied in classifying this variant: BS1,BS2.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	10
DANN	Benign	0.87
DEOGEN2	Benign	0.34	T
Eigen	Benign	-0.96
Eigen_PC	Benign	-0.98
FATHMM_MKL	Benign	0.051	N
LIST_S2	Benign	0.46	T
MetaRNN	Benign	0.0027	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		0.30
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-2.3	N
REVEL	Benign	0.069
Sift	Benign	0.32	T
Sift4G	Benign	0.19	T
Polyphen		0.0020	B
Vest4		0.21
MVP		0.52
MPC		0.083
ClinPred		0.0094	T
GERP RS		1.6
PromoterAI		0.020	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.044
gMVP		0.057
Mutation Taster		=95/5	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		1.0
SpliceAI score (max)		0.060		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs2227945; hg19: chr17-41244130; COSMIC: COSV58797608; COSMIC: COSV58797608;