rs1800744

Positions:

• chr17-43074471-C-A
• chr17-43074471-C-G
• chr17-43074471-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_007294.4(BRCA1):​c.4535G>T​(p.Ser1512Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00308 in 1,614,128 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts 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. S1512C) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.0023 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0032 (17 hom.)
• Consequence: BRCA1 NM_007294.4 missense
• Clinical Significance: Benign reviewed by expert panel B:39 O:1
• Conservation: PhyloP100: 3.21

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.031846404).
• BP6: Variant 17-43074471-C-A is Benign according to our data. Variant chr17-43074471-C-A is described in ClinVar as [Benign]. Clinvar id is 41826.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43074471-C-A is described in Lovd as [Benign]. Variant chr17-43074471-C-A is described in Lovd as [Pathogenic]. Variant chr17-43074471-C-A is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAdExome4 at 17 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA1	NM_007294.4	c.4535G>T	p.Ser1512Ile	missense_variant	14/23	ENST00000357654.9	NP_009225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9	c.4535G>T	p.Ser1512Ile	missense_variant	14/23	1	NM_007294.4	ENSP00000350283.3

Frequencies

GnomAD3 genomes AF: 0.00225 AC: 343 AN: 152166 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000676

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00111

Gnomad ASJ AF: 0.00547

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00123

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.00381

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00237 AC: 596 AN: 251366 Hom.: 1 AF XY: 0.00247 AC XY: 336 AN XY: 135850

Gnomad AFR exome AF: 0.000738

Gnomad AMR exome AF: 0.00173

Gnomad ASJ exome AF: 0.00437

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000490

Gnomad FIN exome AF: 0.00143

Gnomad NFE exome AF: 0.00374

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.00316 AC: 4625 AN: 1461844 Hom.: 17 Cov.: 31 AF XY: 0.00310 AC XY: 2251 AN XY: 727226

Gnomad4 AFR exome AF: 0.000627

Gnomad4 AMR exome AF: 0.00157

Gnomad4 ASJ exome AF: 0.00555

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000696

Gnomad4 FIN exome AF: 0.00137

Gnomad4 NFE exome AF: 0.00367

Gnomad4 OTH exome AF: 0.00273

GnomAD4 genome AF: 0.00226 AC: 344 AN: 152284 Hom.: 0 Cov.: 31 AF XY: 0.00205 AC XY: 153 AN XY: 74466

Gnomad4 AFR AF: 0.000674

Gnomad4 AMR AF: 0.00111

Gnomad4 ASJ AF: 0.00547

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00123

Gnomad4 NFE AF: 0.00382

Gnomad4 OTH AF: 0.00236

Alfa AF: 0.00391 Hom.: 1

Bravo AF: 0.00241

TwinsUK AF: 0.00405 AC: 15

ALSPAC AF: 0.00441 AC: 17

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00395 AC: 34

ExAC AF: 0.00215 AC: 261

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00485

EpiControl AF: 0.00332

ClinVar

Significance: Benign

Submissions summary: Benign:39 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

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

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
Likely benign, no assertion criteria provided	literature only	Pathway Genomics	Jul 24, 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 = 0.00000000000309 -
Benign, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Mar 08, 2011	- -
Benign, criteria provided, single submitter	literature only	Counsyl	Mar 19, 2014	- -
Benign, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA1)	Jun 21, 1999	- -
Benign, criteria provided, single submitter	clinical testing	Michigan Medical Genetics Laboratories, University of Michigan	Nov 03, 2014	- -
Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
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	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 09, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Aug 07, 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 rule this variant out of causing disease. Therefore, this variant is classified as benign. -

not specified Benign:11 Other:1

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Nov 07, 2016	- -
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	Genetic Services Laboratory, University of Chicago	Dec 09, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 10, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jun 15, 2020	- -
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 BRCA1, c.4535G>T, p.Ser1512Ile variant has been reported in the literature in 6/2156 proband chromosomes of individuals with HBOC and sporadic breast/ ovarian cancer. It was also identified in 6/1360 of the control chromosomes evaluated (Al-Mulla_2008, Bergthorsson_2001, Young_2009, Wagner_1998, Tavtigian_2006, Phelan_2005, Sanz_2010). The variant has also been previously identified in our laboratory in 6 individuals, and was classified as benign. The variant is reported in the BIC (x58), Exome Server and BOCs databases. It is also listed in the dbSNP database as coming from a "clinical source" (ID#: rs1800744) with a MAF score of 0.001 (1000 Genomes), increasing the likelihood that this is a low frequency benign variant. The residue is not conserved in mammals, and computational analyses (PolyPhen, SIFT, AlignGVGD) provide inconsistent predictions regarding the impact to the protein. However, this information is not very predictive of pathogenicity. Functional studies examining the effect of the variant on transcriptional activation found that the variant levels were equal to or higher than that of wild type BRCA1, suggesting that it does not represent a high risk variant & is likely to have low clinical significance (Phelan_2005). Studies have also reported that p.Ser1512Ile has been found to co-occur with other known BRCA1 pathogenic variants numerous times, increasing the likelihood that this variant does not have clinical significance (Bergthorsson_2001, Tavtigian_2006, Phelan_2005). In summary, based on the above information, this variant is classified as Benign. -
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	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not provided Benign:5

Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Dec 06, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	BRCA1: BS2 -
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	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 25, 2023	- -

Hereditary breast ovarian cancer syndrome Benign:5

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Likely benign, criteria provided, single submitter	research	Genetics Program, Instituto Nacional de Cancer	Nov 01, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 24, 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, no assertion criteria provided	clinical testing	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	Sep 27, 2021	- -

Hereditary cancer-predisposing syndrome Benign:4

Likely benign, no assertion criteria provided	clinical testing	True Health Diagnostics	Apr 25, 2018	- -
Benign, criteria provided, single submitter	curation	Sema4, Sema4	May 20, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 21, 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	Nov 11, 2014	- -

BRCA1-related cancer predisposition Benign:1

Likely benign, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Sep 27, 2024

- -

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

Dec 23, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.080	T
BayesDel_noAF	Uncertain	0.11
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.25	.;T;.;.;T;.;.;.;T;.
Eigen	Benign	-0.33
Eigen_PC	Benign	-0.41
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.84	T;T;T;T;T;T;T;T;T;T
M_CAP	Pathogenic	0.68	D
MetaRNN	Benign	0.032	T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.12	T
MutationAssessor	Benign	1.9	.;L;.;.;.;.;.;.;.;.
PrimateAI	Benign	0.29	T
PROVEAN	Uncertain	-3.1	D;N;.;D;.;N;D;D;D;D
REVEL	Uncertain	0.52
Sift	Uncertain	0.0030	D;D;.;D;.;D;D;D;D;D
Sift4G	Uncertain	0.014	D;T;D;D;D;T;D;.;.;D
Polyphen		0.34, 0.88	.;B;.;.;.;.;.;.;P;.
Vest4		0.47
MVP		0.85
MPC		0.10
ClinPred		0.033	T
GERP RS		4.0
Varity_R		0.081
gMVP		0.41

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: rs1800744; hg19: chr17-41226488; COSMIC: COSV100523556; COSMIC: COSV100523556;