17-43092507-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BP6_Very_Strong

The NM_007294.4(BRCA1):c.3024G>A(p.Met1008Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000602 in 1,613,918 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M1008V) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.00066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00060 (3 hom.)
• Consequence: BRCA1 NM_007294.4 missense
• Clinical Significance: Benign reviewed by expert panel U:1 B:28 O:1
• Conservation: PhyloP100: -0.569

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009576023).
• BP6: Variant 17-43092507-C-T is Benign according to our data. Variant chr17-43092507-C-T is described in ClinVar as [Benign]. Clinvar id is 41814.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43092507-C-T is described in Lovd as [Benign]. Variant chr17-43092507-C-T is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA1	NM_007294.4	c.3024G>A	p.Met1008Ile	missense_variant	10/23	ENST00000357654.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA1	ENST00000357654.9	c.3024G>A	p.Met1008Ile	missense_variant	10/23	1	NM_007294.4	P4

Frequencies

GnomAD3 genomes AF: 0.000657 AC: 100 AN: 152124 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00203

Gnomad ASJ AF: 0.00894

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.000189

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000368

Gnomad OTH AF: 0.000955

GnomAD3 exomes AF: 0.00102 AC: 256 AN: 251024 Hom.: 1 AF XY: 0.00108 AC XY: 146 AN XY: 135712

Gnomad AFR exome AF: 0.0000618

Gnomad AMR exome AF: 0.00234

Gnomad ASJ exome AF: 0.0111

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000353

Gnomad OTH exome AF: 0.00196

GnomAD4 exome AF: 0.000597 AC: 872 AN: 1461676 Hom.: 3 Cov.: 50 AF XY: 0.000612 AC XY: 445 AN XY: 727142

Gnomad4 AFR exome AF: 0.000508

Gnomad4 AMR exome AF: 0.00224

Gnomad4 ASJ exome AF: 0.00949

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000510

Gnomad4 FIN exome AF: 0.000150

Gnomad4 NFE exome AF: 0.000309

Gnomad4 OTH exome AF: 0.00167

GnomAD4 genome AF: 0.000657 AC: 100 AN: 152242 Hom.: 0 Cov.: 32 AF XY: 0.000645 AC XY: 48 AN XY: 74430

Gnomad4 AFR AF: 0.0000722

Gnomad4 AMR AF: 0.00203

Gnomad4 ASJ AF: 0.00894

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.000189

Gnomad4 NFE AF: 0.000368

Gnomad4 OTH AF: 0.000945

Alfa AF: 0.000831 Hom.: 0

Bravo AF: 0.000963

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000581 AC: 5

ExAC AF: 0.000857 AC: 104

EpiCase AF: 0.000654

EpiControl AF: 0.000296

ClinVar

Significance: Benign

Submissions summary: Uncertain:1 Benign:28 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

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

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 = 0.0000000196 -
Likely benign, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Feb 05, 2024	- -
Uncertain significance, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA1)	May 29, 2002	- -
Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Likely benign, no assertion criteria provided	literature only	Pathway Genomics	Jul 24, 2014	- -
Likely benign, no assertion criteria provided	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Oct 06, 2023	BS1 based on allele frequency in AJ population of 0.010807 in gnomAD. REVEL score of 0.452. PMID:23867111 showed function like WT. -
Benign, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Oct 23, 2012	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Aug 14, 2019	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. -
Benign, criteria provided, single submitter	literature only	Counsyl	Jan 24, 2014	- -
Benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	Also identified by our lab once in an individual with a second pathogenic mutation AJ mutation - JLE -
Benign, no assertion criteria provided	clinical testing	BRCAlab, Lund University	Mar 02, 2020	- -

not specified Benign:6 Other:1

Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 29, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: ExAC: 0.2% (25/11568) Latino; ClinVar: 5 B/LB, 3 VUS -
Benign, criteria provided, single submitter	clinical testing	Cancer Genetics and Genomics Laboratory, British Columbia Cancer Agency	Apr 18, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 12, 2015	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Jan 30, 2017	- -
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	Genetic Services Laboratory, University of Chicago	Jun 22, 2018	- -

Hereditary cancer-predisposing syndrome Benign:4

Benign, criteria provided, single submitter	curation	Sema4, Sema4	Feb 24, 2020	- -
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. -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Feb 11, 2015	- -
Benign, no assertion criteria provided	clinical testing	True Health Diagnostics	Sep 28, 2018	- -

Hereditary breast ovarian cancer syndrome Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	Apr 25, 2016	- -
Benign, criteria provided, single submitter	clinical testing	National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	Nov 16, 2021	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jul 08, 2022	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	BRCA1: BP4, BS1, BS2 -

Breast and/or ovarian cancer Benign:1

Benign, criteria provided, single submitter

clinical testing

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

May 05, 2023

- -

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

Sep 02, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.30
Cadd	Benign	0.11
Dann	Benign	0.50
DEOGEN2	Benign	0.10	T;.;.;.
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.030	N
LIST_S2	Benign	0.63	T;T;T;T
M_CAP	Benign	0.033	D
MetaRNN	Benign	0.0096	T;T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.64	N;N;.;.
MutationTaster	Benign	1.0	N;N;N;N;N;N;N;N;N;N;N;N;N;N
PrimateAI	Benign	0.20	T
PROVEAN	Benign	-0.48	N;N;N;N
REVEL	Uncertain	0.45
Sift	Benign	0.52	T;T;T;T
Sift4G	Benign	0.58	T;T;T;T
Polyphen		0.0	B;.;.;B
Vest4		0.23
MutPred		0.17		Gain of catalytic residue at P1010 (P = 0.0368);Gain of catalytic residue at P1010 (P = 0.0368);.;Gain of catalytic residue at P1010 (P = 0.0368);
MVP		0.35
MPC		0.090
ClinPred		0.0022	T
GERP RS		-4.1
Varity_R		0.028
gMVP		0.11

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: rs1800704; hg19: chr17-41244524; COSMIC: COSV58794365; COSMIC: COSV58794365;