17-43063351-T-C

Position:

• chr17-43063351-T-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6_Very_Strong BP7

The ENST00000357654.9(BRCA1):​c.5175A>G​(p.Glu1725=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000434 in 1,611,322 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000045 (0 hom.)
• Consequence: BRCA1 ENST00000357654.9 synonymous
• Clinical Significance: Likely benign reviewed by expert panel B:19 O:1
• Conservation: PhyloP100: 2.41

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.69).
• BP6: Variant 17-43063351-T-C is Benign according to our data. Variant chr17-43063351-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 136552.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43063351-T-C is described in Lovd as [Benign]. Variant chr17-43063351-T-C is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=2.41 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA1	NM_007294.4	c.5175A>G	p.Glu1725=	synonymous_variant	18/23	ENST00000357654.9	NP_009225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9	c.5175A>G	p.Glu1725=	synonymous_variant	18/23	1	NM_007294.4	ENSP00000350283	P4

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152250 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000956 AC: 24 AN: 251166 Hom.: 0 AF XY: 0.0000663 AC XY: 9 AN XY: 135768

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000405

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000616

Gnomad OTH exome AF: 0.000491

GnomAD4 exome AF: 0.0000452 AC: 66 AN: 1458954 Hom.: 0 Cov.: 30 AF XY: 0.0000455 AC XY: 33 AN XY: 726066

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000313

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000352

Gnomad4 OTH exome AF: 0.000199

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152368 Hom.: 0 Cov.: 32 AF XY: 0.0000268 AC XY: 2 AN XY: 74524

Gnomad4 AFR AF: 0.0000240

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000676 Hom.: 0

Bravo AF: 0.0000680

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Likely benign

Submissions summary: Benign:19 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1 Benign:5 Other:1

Benign, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Dec 18, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Benign, criteria provided, single submitter	clinical testing	University of Science and Technology Houari Boumediene, Laboratory of Molecular and Cellular Biology (LBCM)	-	- -
Likely benign, reviewed by expert panel	curation	Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	Jun 29, 2017	Synonymous substitution variant, with low bioinformatic likelihood to result in a splicing aberration (Splicing prior probability 0.02; http://priors.hci.utah.edu/PRIORS/). -
not provided, no classification provided	in vitro	Brotman Baty Institute, University of Washington	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Counsyl	May 03, 2016	- -

not provided Benign:4

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 17, 2017	Variant summary: The BRCA1 c.5175A>G (p.Glu1725Glu) variant involves the alteration of a conserved nucleotide causing a synonymous change, which 5/5 splice prediction tools predict no significant impact on normal splicing or ESE binding. A functional study, Quiles_2016, support these predictions. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 4/120394 (1/30120), which does not exceed the estimated maximal expected allele frequency for a pathogenic BRCA1 variant of 1/1000. Multiple publications have cited the variant in affected individuals, although with limited information (ie, no co-occurrence and cosegregation data). A reputable database cites the variant in 14 individuals with a classification of "likely neutral," with 3 of the individuals carrying another pathogenic BRCA variant, 1 BRCA1, c.3839_3843delinsAGGC (p.Ser1280X) and 2 BRCA2s, c.1310_1313delAAGA (p.Lys437IlefsX22) and c.7234insG (p.Thr2412AspfsX2). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign/likely benign. Therefore, taking all availble lines of evidence into consideration, the variant of interest has been classified as "likely benign." -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jul 17, 2019	- -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Hereditary cancer-predisposing syndrome Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 02, 2018	This alteration is classified as likely 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	curation	Sema4, Sema4	Feb 13, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Dec 28, 2015	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 27, 2014	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. -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Apr 16, 2019	- -

Hereditary breast ovarian cancer syndrome Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 28, 2024	- -
Likely benign, criteria provided, single submitter	research	Genetics Program, Instituto Nacional de Cancer	Nov 01, 2021	- -

Breast and/or ovarian cancer Benign:1

Likely benign, criteria provided, single submitter

clinical testing

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

May 27, 2022

- -

Malignant tumor of breast Benign:1

Likely benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The BRCA1 The p.Glu1725= variant was identified in 5 of 1304 proband chromosomes (frequency: 0.004) from Spanish and Algerian individuals or families with (familial or sporadic) breast or ovarian cancers, and was not identified in 385 control chromosomes from healthy individuals (Cherbal 2012 22684231, Uhrhammer 2008 18645608, Infante 2006 16758124, Beristain_2007_17262179). RNA transcript analysis of the variant from cultured lymphocytes showed the variant had no effect on splicing (Quiles_2016_26780556). The variant was also identified in dbSNP (ID: rs191373374) as “With Likely benign allele, Uncertain Significance allele”, the ClinVar database (classified benign, reviewed by an expert panel (2017); submitters: benign by GeneDX and Invitae, and likely benign by ENIGMA, Ambry Genetics and Counsyl) and Clinvitae, but was not in GeneInSight-COGR, COSMIC, MutDB, UMD, BIC, ARUP , LOVD, 1000 Genomes Project, the NHLBI GO Exome Sequencing Project, the Exome Aggregation Consortium (August 8th 2016) or the Genome Aggregation Consortium (Feb 27, 2017) control databases.. The p.Glu1725= variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. In addition, only 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predicts a greater than 10% chance that the variant creates a cryptic 3' acceptor splice site; however, this information is not very predictive of pathogenicity. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -

BRCA1-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 21, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
CADD	Benign	7.4
DANN	Benign	0.55
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6

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: rs191373374; hg19: chr17-41215368;