chr17-43091016-C-T

Position:

• chr17-43091016-C-T

Variant summary

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

The NM_007294.4(BRCA1):​c.4113G>A​(p.Gly1371Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000261 in 1,612,698 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.0013 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00015 (0 hom.)
• Consequence: BRCA1 NM_007294.4 synonymous
• Clinical Significance: Likely benign reviewed by expert panel B:26
• Conservation: PhyloP100: -0.549

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=-0.61).
• BP6: Variant 17-43091016-C-T is Benign according to our data. Variant chr17-43091016-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 136547.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43091016-C-T is described in Lovd as [Likely_benign]. Variant chr17-43091016-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.549 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA1	NM_007294.4	c.4113G>A	p.Gly1371Gly	synonymous_variant	11/23	ENST00000357654.9	NP_009225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9	c.4113G>A	p.Gly1371Gly	synonymous_variant	11/23	1	NM_007294.4	ENSP00000350283.3

Frequencies

GnomAD3 genomes AF: 0.00136 AC: 207 AN: 152206 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00475

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

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: 0.0000147

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.000374 AC: 93 AN: 248710 Hom.: 0 AF XY: 0.000253 AC XY: 34 AN XY: 134364

Gnomad AFR exome AF: 0.00471

Gnomad AMR exome AF: 0.000408

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: 0.0000178

Gnomad OTH exome AF: 0.000329

GnomAD4 exome AF: 0.000148 AC: 216 AN: 1460374 Hom.: 0 Cov.: 32 AF XY: 0.000109 AC XY: 79 AN XY: 726326

Gnomad4 AFR exome AF: 0.00442

Gnomad4 AMR exome AF: 0.000427

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: 0.00000900

Gnomad4 OTH exome AF: 0.000597

GnomAD4 genome AF: 0.00135 AC: 205 AN: 152324 Hom.: 1 Cov.: 32 AF XY: 0.00132 AC XY: 98 AN XY: 74482

Gnomad4 AFR AF: 0.00471

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000680 Hom.: 0

Bravo AF: 0.00141

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.0000595

ClinVar

Significance: Likely benign

Submissions summary: Benign:26

Revision: reviewed by expert panel

Submissions by phenotype

not specified Benign:5

Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 26, 2014	- -
Likely 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	GeneDx	Feb 25, 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	Mar 03, 2020	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Jul 14, 2017	- -

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

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/). -
Likely 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	Illumina Laboratory Services, Illumina	Dec 06, 2017	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	clinical testing	University of Science and Technology Houari Boumediene, Laboratory of Molecular and Cellular Biology (LBCM)	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

not provided Benign:5

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jul 08, 2022	- -

Hereditary breast ovarian cancer syndrome Benign:5

Likely benign, criteria provided, single submitter	research	Genetics Program, Instituto Nacional de Cancer	Nov 01, 2021	- -
Likely 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	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	Jan 24, 2023	- -
Benign, no assertion criteria provided	research	Hereditary Cancer Genetics group, Vall d'Hebron Institute of Oncology	Mar 01, 2019	- -

Hereditary cancer-predisposing syndrome Benign:3

Benign, criteria provided, single submitter	curation	Sema4, Sema4	Nov 19, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 12, 2014	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	clinical testing	Color Diagnostics, LLC DBA Color Health	Jul 28, 2015	- -

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

Mar 01, 2023

- -

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 p.Gly1371Gly variant was identified in 1 of 158 proband chromosomes (frequency: 0.006) from individuals or families with breast and colon cancer, and was not identified in 200 control chromosomes from healthy individuals (Cherbal 2012). The variant was also previously identified by our laboratory in 1 individual with breast cancer. The variant was identified in dbSNP (ID: rs147448807), with a minor allele frequency of 0.0016 (1000 Genomes Project), NHLBI GO Exome Sequencing Project in 16 of 4406 alleles (freq.0.004). The variant was identified in the Exome Aggregation Consortium database (March 14, 2016) in 50 of 99796 chromosomes (freq. 0.000501) in the following populations: African in 45 of 8594 chromosomes (freq. 0.005236), European (Non-Finnish) in 2 of 54166 chromosomes (freq. 0.00003692), Latino in 3 of 9428 chromosomes (freq. 0.0003182), but was not seen in East Asian, European (Finnish), South Asian and Other populations, increasing the likelihood that this may be a low frequency benign variant in certain populations of origin; the ClinVar database (classified as a benign variant by GeneDx, Invitae and likely benign by Ambry Genetics, Emory Genetics Laboratory), GeneInsight COGR (2x, classified benign and as uncertain significance) and BRCA Share UMD (38x as likely neutral). In UMD the variant was identified with co-occurring pathogenic BRCA1 and BRCA2 variants (BRCA1 c.342_343delTC p.Pro115X, c.1423_1508del p.Ser475AlafsX2 and BRCA2 c.6984delG p.Glu2328AspfsX39, c.4889C>G, p.Ser1630X) increasing the likelihood that the p.Gly1371Gly variant does not have clinical significance. The p.Gly1371Gly 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. The p.Gly1371Gly variant occurs outside of the splicing consensus sequence and 2 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this 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. -

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
BayesDel_noAF	Benign	-0.61
CADD	Benign	1.0
DANN	Benign	0.54

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs147448807; hg19: chr17-41243033;