rs80356839

chr17-43124022-G-Achr17-43124022-G-Cchr17-43124022-G-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.75C>T(p.Pro25=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000596 in 1,610,856 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 Likely benign (★★★). Synonymous variant affecting the same amino acid position (i.e. P25P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000062 (3 hom.)
• Consequence: BRCA1 NM_007294.4 synonymous
• Clinical Significance: Likely benign reviewed by expert panel B:20
• Conservation: PhyloP100: -0.455

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=-0.57).
• BP6: Variant 17-43124022-G-A is Benign according to our data. Variant chr17-43124022-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 55691.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43124022-G-A is described in Lovd as [Benign]. Variant chr17-43124022-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.455 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA1	NM_007294.4	c.75C>T	p.Pro25=	synonymous_variant	2/23	ENST00000357654.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA1	ENST00000357654.9	c.75C>T	p.Pro25=	synonymous_variant	2/23	1	NM_007294.4	P4

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152148 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000955

GnomAD3 exomes AF: 0.0000239 AC: 6 AN: 251038 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135668

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000326

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000617 AC: 90 AN: 1458708 Hom.: 3 Cov.: 30 AF XY: 0.0000386 AC XY: 28 AN XY: 725934

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000504

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00113

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152148 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74326

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000385

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000955

Alfa AF: 0.000174 Hom.: 0

Bravo AF: 0.0000756

Asia WGS AF: 0.00664 AC: 23 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:20

Revision: reviewed by expert panel

Submissions by phenotype

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	Cancer Genetics and Genomics Laboratory, British Columbia Cancer Agency	Apr 18, 2017	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	research	King Laboratory, University of Washington	Sep 01, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Department of Pathology and Molecular Medicine, Queen's University	Apr 20, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -

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, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	May 24, 2017	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -

Breast-ovarian cancer, familial, susceptibility to, 1 Benign:3

Benign, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA1)	Jul 19, 2006	- -
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	- -

Hereditary cancer-predisposing syndrome Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Apr 13, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Aug 04, 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	curation	Sema4, Sema4	Feb 03, 2021	- -

Hereditary breast ovarian cancer syndrome Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	Oct 17, 2023	- -

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

Jun 14, 2021

- -

Malignant tumor of breast Benign:1

Benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The BRCA1 p.Pro25Pro variant was identified in the literature (Bowles_2014_Myriad Publ, Ozcelik H_2012_22874498). However, no proband information was available. The variant was identified in dbSNP (ID: rs80356839) “With Likely benign allele”, Exome Aggregation Consortium (ExAC) database (released Oct 20th, 2014) in 4 of 120942 chromosomes (frequency: 3.31e-05) from a population of East Asian (4 of 8640 chromosomes) The variant was not found in African, Latino, South Asian, European (Finnish), European (Non-Finnish) and other individuals. The variant was also identified in the ClinVar database (classified as a Benign by BIC and Gene DX and as Likely Benign by Invitae), GeneInsight through the Canadian Open Genetics Repository (http://opengenetics.ca/) (2X, classified as “IARC1 and IARC2” by 2 clinical laboratories), the BIC database (1X with unknown clinical importance).The variant was also previously identified by our laboratory 6X.The Pro25Pro 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, in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. Additionally, at the ACMG Meeting in March 2014, ( Bowles_2014_Myriad Publ) Myriad announced that “BRCA1 c.75C>T (p.Pro25Pro) has been previously observed in a patient with decreased mRNA transcript levels and was postulated to be pathogenic. However, in Myriad’s patient population, this variant co-occurs in trans with known deleterious BRCA1 mutations in five patients and has been found in the homozygous state in 14 patients, strongly indicating a benign classification. History weighting analysis confirms the benign nature of this variant.” In summary, based on the above information, this variant meets our laboratory's criteria to be classified as 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	-0.57
Cadd	Benign	8.4
Dann	Benign	0.82
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs80356839; hg19: chr17-41276039;