chr17-43092113-T-C

Position:

• chr17-43092113-T-C

Variant summary

Our verdict is Benign. Variant got -24 ACMG points: 0P and 24B. BP5_Strong BP1_Strong BS3 BS2 BA1

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

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 -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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA1	NM_007294.4	c.3418A>G	p.Ser1140Gly	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.3418A>G	p.Ser1140Gly	missense_variant	10/23	1	NM_007294.4	ENSP00000350283.3

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

GnomAD3 exomes AF: 0.00252 AC: 633 AN: 251092 Hom.: 12 AF XY: 0.00166 AC XY: 226 AN XY: 135768

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 SAS exome AF: 0.0000653

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

Gnomad4 AFR exome AF: 0.0350

Gnomad4 AMR exome AF: 0.00192

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000696

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000117

Gnomad4 OTH exome AF: 0.00217

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

Gnomad4 AFR AF: 0.0341

Gnomad4 AMR AF: 0.00235

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000162

Gnomad4 OTH AF: 0.00662

Alfa AF: 0.00270 Hom.: 6

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

Uncertain significance, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA1)	May 29, 2002	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Feb 22, 2018	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. -
Likely benign, criteria provided, single submitter	literature only	Counsyl	Jan 02, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Michigan Medical Genetics Laboratories, University of Michigan	Nov 03, 2014	- -
Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -
Benign, no assertion criteria provided	clinical testing	Department of Medical Genetics, University Hospital of North Norway	May 01, 2016	- -
Benign, no assertion criteria provided	clinical testing	BRCAlab, Lund University	Mar 02, 2020	- -

not specified Benign:7 Other:1

Benign, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -
Benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	May 05, 2017	- -
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	-	- -
Benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	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. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 03, 2014	- -

not provided Benign:5

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2024	BRCA1: BP4, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jun 01, 2023	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Oct 09, 2017	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, no assertion criteria provided	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jul 13, 2012	- -

Hereditary breast ovarian cancer syndrome Benign:5

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	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 15, 2013	- -
Likely benign, criteria provided, single submitter	clinical testing	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	Feb 14, 2017	- -
Benign, criteria provided, single submitter	research	Genetics Program, Instituto Nacional de Cancer	Nov 01, 2021	- -

Hereditary cancer-predisposing syndrome Benign:4

Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Nov 18, 2014	- -
Benign, criteria provided, single submitter	curation	Sema4, Sema4	Mar 26, 2020	- -
Benign, no assertion criteria provided	clinical testing	True Health Diagnostics	Jan 03, 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. -

Breast and/or ovarian cancer Benign:1

Benign, criteria provided, single submitter

clinical testing

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

Jul 06, 2021

- -

BRCA1-related cancer predisposition Benign:1

Benign, reviewed by expert panel

curation

ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen

Jun 11, 2024

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

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 21, 2021

- -

Familial cancer of breast Benign:1

Benign, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Sep 25, 2018

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

Computational scores

Source: dbNSFP v4.3

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;T;T;T
MetaRNN	Benign	0.0027	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.4	M;M;.;.
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-2.3	N;N;N;N
REVEL	Benign	0.069
Sift	Benign	0.32	T;T;T;T
Sift4G	Benign	0.19	T;T;T;T
Polyphen		0.0020	B;.;.;B
Vest4		0.21
MVP		0.52
MPC		0.083
ClinPred		0.0094	T
GERP RS		1.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.044
gMVP		0.057

Splicing

Name	Calibrated prediction	Score	Prediction
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

Publications

LitVar

Other links and lift over

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