17-43092412-C-T

Position:

• chr17-43092412-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_007294.4(BRCA1):​c.3119G>A​(p.Ser1040Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0193 in 1,613,846 control chromosomes in the GnomAD database, including 338 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S1040G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.014 (20 hom., cov: 32)
  • Exomes 𝑓: 0.020 (318 hom.)
• Consequence: BRCA1 NM_007294.4 missense
• Clinical Significance: Benign reviewed by expert panel U:2 B:40 O:1
• Conservation: PhyloP100: -0.0250

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005789846).
• BP6: Variant 17-43092412-C-T is Benign according to our data. Variant chr17-43092412-C-T is described in ClinVar as [Benign]. Clinvar id is 17670.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43092412-C-T is described in Lovd as [Benign]. Variant chr17-43092412-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0143 (2177/152184) while in subpopulation NFE AF= 0.0215 (1464/67996). AF 95% confidence interval is 0.0206. There are 20 homozygotes in gnomad4. There are 966 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 20 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA1	NM_007294.4	c.3119G>A	p.Ser1040Asn	missense_variant	10/23	ENST00000357654.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA1	ENST00000357654.9	c.3119G>A	p.Ser1040Asn	missense_variant	10/23	1	NM_007294.4	P4

Frequencies

GnomAD3 genomes AF: 0.0143 AC: 2178 AN: 152066 Hom.: 20 Cov.: 32

Gnomad AFR AF: 0.00454

Gnomad AMI AF: 0.0822

Gnomad AMR AF: 0.0174

Gnomad ASJ AF: 0.0239

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00601

Gnomad FIN AF: 0.00283

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0215

Gnomad OTH AF: 0.0187

GnomAD3 exomes AF: 0.0132 AC: 3302 AN: 251032 Hom.: 26 AF XY: 0.0134 AC XY: 1824 AN XY: 135674

Gnomad AFR exome AF: 0.00523

Gnomad AMR exome AF: 0.0102

Gnomad ASJ exome AF: 0.0195

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00542

Gnomad FIN exome AF: 0.00283

Gnomad NFE exome AF: 0.0206

Gnomad OTH exome AF: 0.0175

GnomAD4 exome AF: 0.0198 AC: 28896 AN: 1461662 Hom.: 318 Cov.: 41 AF XY: 0.0195 AC XY: 14177 AN XY: 727116

Gnomad4 AFR exome AF: 0.00412

Gnomad4 AMR exome AF: 0.0112

Gnomad4 ASJ exome AF: 0.0194

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00595

Gnomad4 FIN exome AF: 0.00375

Gnomad4 NFE exome AF: 0.0233

Gnomad4 OTH exome AF: 0.0169

GnomAD4 genome AF: 0.0143 AC: 2177 AN: 152184 Hom.: 20 Cov.: 32 AF XY: 0.0130 AC XY: 966 AN XY: 74424

Gnomad4 AFR AF: 0.00453

Gnomad4 AMR AF: 0.0174

Gnomad4 ASJ AF: 0.0239

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00581

Gnomad4 FIN AF: 0.00283

Gnomad4 NFE AF: 0.0215

Gnomad4 OTH AF: 0.0185

Alfa AF: 0.0201 Hom.: 75

Bravo AF: 0.0159

TwinsUK AF: 0.0259 AC: 96

ALSPAC AF: 0.0244 AC: 94

ESP6500AA AF: 0.00613 AC: 27

ESP6500EA AF: 0.0219 AC: 188

ExAC AF: 0.0132 AC: 1598

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.0243

EpiControl AF: 0.0238

ClinVar

Significance: Benign

Submissions summary: Uncertain:2 Benign:40 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1 Uncertain:2 Benign:12

Benign, criteria provided, single submitter	clinical testing	Michigan Medical Genetics Laboratories, University of Michigan	Nov 03, 2014	- -
Benign, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Mar 14, 2011	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	literature only	Counsyl	Jan 20, 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 0.02111 (European), derived from 1000 genomes (2012-04-30). -
Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 09, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -
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, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
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	Mendelics	May 28, 2019	- -
Likely benign, no assertion criteria provided	literature only	Pathway Genomics	Jul 24, 2014	- -
Uncertain significance, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA1)	May 29, 2002	- -
Uncertain significance, no assertion criteria provided	literature only	OMIM	Nov 01, 2012	- -

not specified Benign:11 Other:1

not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 29, 2015	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneKor MSA	Nov 01, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jun 15, 2020	- -
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	Department of Pathology and Laboratory Medicine, Sinai Health System	-	- -
Benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	Cancer Genetics and Genomics Laboratory, British Columbia Cancer Agency	Apr 18, 2017	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 14, 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, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -

not provided Benign:5

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 28, 2023	- -
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	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	BRCA1: BP4, BS1, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jan 19, 2017	- -

Hereditary cancer-predisposing syndrome Benign:5

Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Nov 05, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Vantari Genetics	Nov 27, 2015	- -
Benign, no assertion criteria provided	clinical testing	True Health Diagnostics	Nov 14, 2017	- -
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. -
Benign, criteria provided, single submitter	curation	Sema4, Sema4	May 03, 2021	- -

Hereditary breast ovarian cancer syndrome Benign:5

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 08, 2014	- -
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	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	- -
Likely benign, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Apr 14, 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 16, 2022

- -

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	0.12
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	14
DANN	Uncertain	0.99
DEOGEN2	Benign	0.40	T;.;.;.
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.30
FATHMM_MKL	Benign	0.021	N
LIST_S2	Benign	0.81	T;T;T;T
MetaRNN	Benign	0.0058	T;T;T;T
MetaSVM	Benign	-0.55	T
MutationAssessor	Uncertain	2.0	M;M;.;.
MutationTaster	Benign	1.0	N;N;N;N;N;N;N;N;N;N;N;N;N;N
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-1.7	N;N;N;N
REVEL	Uncertain	0.38
Sift	Benign	0.084	T;T;T;T
Sift4G	Benign	0.066	T;T;T;D
Polyphen		0.97	D;.;.;B
Vest4		0.21
MPC		0.13
ClinPred		0.0054	T
GERP RS		2.0
Varity_R		0.053
gMVP		0.12

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: rs4986852; hg19: chr17-41244429; COSMIC: COSV58791858; COSMIC: COSV58791858;