17-43094550-T-C

Position:

• chr17-43094550-T-C

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_007294.4(BRCA1):​c.981A>G​(p.Thr327Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000602 in 1,614,214 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.00066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00060 (3 hom.)
• Consequence: BRCA1 NM_007294.4 synonymous
• Clinical Significance: Benign reviewed by expert panel U:1 B:25
• Conservation: PhyloP100: -0.133

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]

BRCA1 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.71).
• BP6: Variant 17-43094550-T-C is Benign according to our data. Variant chr17-43094550-T-C is described in ClinVar as [Benign]. Clinvar id is 55771.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43094550-T-C is described in Lovd as [Benign]. Variant chr17-43094550-T-C is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.133 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome4 at 3 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA1	NM_007294.4	c.981A>G	p.Thr327Thr	synonymous_variant	10/23	ENST00000357654.9	NP_009225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9	c.981A>G	p.Thr327Thr	synonymous_variant	10/23	1	NM_007294.4	ENSP00000350283.3

Frequencies

GnomAD3 genomes AF: 0.000657 AC: 100 AN: 152254 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00196

Gnomad ASJ AF: 0.00893

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000367

Gnomad OTH AF: 0.000955

GnomAD3 exomes AF: 0.00101 AC: 255 AN: 251408 Hom.: 1 AF XY: 0.00107 AC XY: 146 AN XY: 135860

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00231

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: 0.000352

Gnomad OTH exome AF: 0.00196

GnomAD4 exome AF: 0.000597 AC: 872 AN: 1461842 Hom.: 3 Cov.: 34 AF XY: 0.000613 AC XY: 446 AN XY: 727222

Gnomad4 AFR exome AF: 0.000538

Gnomad4 AMR exome AF: 0.00221

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: 0.000656 AC: 100 AN: 152372 Hom.: 0 Cov.: 32 AF XY: 0.000644 AC XY: 48 AN XY: 74514

Gnomad4 AFR AF: 0.0000962

Gnomad4 AMR AF: 0.00196

Gnomad4 ASJ AF: 0.00893

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.000367

Gnomad4 OTH AF: 0.000945

Alfa AF: 0.00119 Hom.: 0

Bravo AF: 0.000963

EpiCase AF: 0.000654

EpiControl AF: 0.000296

ClinVar

Significance: Benign

Submissions summary: Uncertain:1 Benign:25

Revision: reviewed by expert panel

Submissions by phenotype

not specified Benign:8

Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 12, 2015	- -
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	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Jan 30, 2017	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The p.Thr327Thr variant is not expected to have clinical significance because it does not alter an amino acid residue and is not located near a splice junction. It has been reported in the literature in 14/10588 proband chromosomes from individuals with hereditary and sporadic breast and/ or ovarian carcer (Alsop_2012_22711857, Borg_2010_20104584, Caux-Moncoutier_2011_21120943, Malone_1998_9544766, Stoppa-Lyonnet_1997_9150149, Tazzite_2012_22425665, Uhrhammer_2008_18645608); but it was not identified in the limited number (142) of control chromosomes evaluated. It is listed in dbSNP as coming from a "clinical source" (ID#: rs1800063), but no frequency information was provided, and so the prevalence of this variant in the general population is not known. The variant has been identified in the BIC database (x1), UMD database (x30) as likely neutral, and classified in the BOCs database (x1) as benign (ACMG 5). In addition, this variant has been identified by our laboratory in one individual with a second pathogenic mutation, increasing the likelihood this variant is benign. In summary, based on the above information, the p.Arg3370Arg variant is classified as benign. -
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	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Jan 18, 2017	- -

Breast-ovarian cancer, familial, susceptibility to, 1 Uncertain:1 Benign:6

Uncertain significance, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA1)	Jul 08, 2011	- -
Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Likely benign, criteria provided, single submitter	literature only	Counsyl	Jan 24, 2014	- -
Benign, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Mar 02, 2011	- -
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 alter mRNA splicing (splicing prior 0.02; http://priors.hci.utah.edu/PRIORS/) and frequency 0.0021 (Admixed American/Latino), derived from ExAC (2014-12-17). -
Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -

not provided Benign:5

Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jul 08, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	BRCA1: BP4, BP7 -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Hereditary cancer-predisposing syndrome Benign:3

Likely benign, no assertion criteria provided	clinical testing	True Health Diagnostics	Sep 28, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Apr 27, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 25, 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. -

Hereditary breast ovarian cancer syndrome Benign:3

Benign, criteria provided, single submitter	clinical testing	National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	Nov 16, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, no assertion criteria provided	clinical testing	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	Dec 17, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
CADD	Benign	5.9
DANN	Benign	0.66

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: rs1800063; hg19: chr17-41246567;