17-43071102-T-C

Variant names:

• chr17-43071102-T-C
• rs28897693
• NM_007294.4:c.4812A>G

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.4812A>G​(p.Gln1604Gln) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00109 in 1,614,140 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.00074 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (16 hom.)
• Consequence: BRCA1 NM_007294.4 synonymous
• Clinical Significance: Benign reviewed by expert panel U:2 B:26
• Conservation: PhyloP100: -1.88

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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 17-43071102-T-C is Benign according to our data. Variant chr17-43071102-T-C is described in ClinVar as [Benign]. Clinvar id is 55293.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43071102-T-C is described in Lovd as [Benign]. Variant chr17-43071102-T-C is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-1.88 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome4 at 16 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA1	NM_007294.4	c.4812A>G	p.Gln1604Gln	synonymous_variant	Exon 15 of 23	ENST00000357654.9	NP_009225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9	c.4812A>G	p.Gln1604Gln	synonymous_variant	Exon 15 of 23	1	NM_007294.4	ENSP00000350283.3

Frequencies

GnomAD3 genomes AF: 0.000742 AC: 113 AN: 152194 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00455

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00122

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00110 AC: 276 AN: 251404 Hom.: 5 AF XY: 0.00114 AC XY: 155 AN XY: 135868

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.000318

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000272

Gnomad SAS exome AF: 0.00438

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000994

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.00113 AC: 1654 AN: 1461828 Hom.: 16 Cov.: 33 AF XY: 0.00121 AC XY: 879 AN XY: 727220

Gnomad4 AFR exome AF: 0.000119

Gnomad4 AMR exome AF: 0.000336

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000504

Gnomad4 SAS exome AF: 0.00383

Gnomad4 FIN exome AF: 0.0000374

Gnomad4 NFE exome AF: 0.00110

Gnomad4 OTH exome AF: 0.00101

GnomAD4 genome AF: 0.000735 AC: 112 AN: 152312 Hom.: 0 Cov.: 32 AF XY: 0.000698 AC XY: 52 AN XY: 74484

Gnomad4 AFR AF: 0.000168

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00456

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00121

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000818 Hom.: 0

Bravo AF: 0.000570

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000981

EpiControl AF: 0.000711

ClinVar

Significance: Benign

Submissions summary: Uncertain:2 Benign:26

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1 Uncertain:2 Benign:7

Feb 01, 2025

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 28, 2017

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Jan 02, 2014

Counsyl

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: literature only

- -

Mar 02, 2020

BRCAlab, Lund University

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jun 29, 2017

Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)

Significance: Benign

Review Status: reviewed by expert panel

Collection Method: curation

Synonymous substitution variant, with low bioinformatic likelihood to alter mRNA splicing (splicing prior 0.02; http://priors.hci.utah.edu/PRIORS/) and frequency 0.0043 (South Asian), derived from ExAC (2014-12-17). -

Jul 08, 2011

Breast Cancer Information Core (BIC) (BRCA1)

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Dec 29, 2014

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 21, 2015

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:6

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

The BRCA1 p.Gln1604Gln variant was identified in 4 of 2576 proband chromosomes (frequency: 0.001) from Danish, Korean, and American individuals or families with breast and ovarian cancers, and was identified in 5 of 7138 (freq. 0.001) control chromosomes from healthy individuals (Bergthorsson 2001, Kim 2006, McKean-Cowdin 2005). The variant was identified in dbSNP (ID: rs28897693) as “Other”, Fanconi Anemia Mutation Database-LOVD (8x as unknown or unclassified), the ClinVar and Clinvitae databases (conflicting interpretations, classification benign by GeneDx and Invitae, likely benign by Counsyl, Ambry Genetics, and CHEO, and uncertain significance by BIC), GeneInsight COGR database (4x, classified as benign and likely benign by clinical laboratories), the BIC database (4x with unknown clinical importance, classification pending), and UMD (89x with a “likely neutral” classification). In UMD the variant was identified with co-occurring pathogenic BRCA1 variants (c.4065_4068delTCAA, p.Asn1355LysfsX10 and c.68_69delAG, p.Glu23ValfsX17), and BRCA2 variant (c.3847_3848delGT, p.Val1283LysfsX2), increasing the likelihood that the p.Gln1604Gln variant does not have clinical significance. This variant was identified in the 1000 Genomes Project in 7 of 5000 chromosomes (frequency: 0.0014); HAPMAP-EUR in 2 of 1006 chromosomes (frequency: 0.002), and HAPMAP-SAS in 5 of 978 chromosomes (frequency: 0.005); the NHLBI GO Exome Sequencing Project in 12 of 8600 European American alleles and in 6 of 4406 African American alleles; the genome Aggregation Database (February 27, 2017) in 294 (5 homozygous) of 282582 chromosomes (freq. 0.001); and the Exome Aggregation Consortium database (August 8th 2016) in 156 (2 homozygous) of 121402 chromosomes (freq. 0.001) in the following populations: Other in 5 of 908 chromosomes (freq. 0.006), South Asian in 71 of 16512 chromosomes (freq. 0.004), European (Non-Finnish) in 67 of 66738 chromosomes (freq. 0.001), African in 7 of 10406 chromosomes (freq. 0.0006), and East Asian in 4 of 8654 chromosomes (freq. 0.0005), Latino in 2 of 11570 chromosomes (freq. 0.0002) but was not seen in Finnish population; increasing the likelihood this could be a low frequency benign variant. The variant was (also) identified by our laboratory in 1 individual with breast cancer. The p.Gln1604Gln 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) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information, this variant meets our laboratory's criteria to be classified as benign. -

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 14, 2019

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 18, 2013

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

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Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Benign:4

May 15, 2017

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Oct 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BRCA1: BP4, BP7, BS2 -

Jan 22, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Benign:4

Jul 03, 2014

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

-

Color Diagnostics, LLC DBA Color Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 28, 2020

Sema4, Sema4

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Apr 25, 2018

True Health Diagnostics

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Hereditary breast ovarian cancer syndrome Benign:3

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 16, 2021

National Health Laboratory Service, Universitas Academic Hospital and University of the Free State

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 24, 2020

Genetics and Molecular Pathology, SA Pathology

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The BRCA1 c.4812A>G variant is classified as Benign (BS1, BP6_Strong, BP4) This BRCA1 c.4812A>G variant is synonymous (silent). The frequency of this variant in population databases is higher than expected for this disorder (BS1). Multiple lines of computational evidence suggest this variant has no impact on the gene or gene product (BP4). The variant has been reported in dbSNP (rs28897693) and has been reported as Benign by other diagnostic laboratories (ClinVar Variation ID: 55293). It has not been reported in HGMD. literature: Seen in 7 patients with breast cancer (Borg et al., 2010 PMID: 20104584). -

Breast and/or ovarian cancer Benign:1

Apr 13, 2023

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

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Familial cancer of breast Benign:1

Feb 23, 2017

Baylor Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.10
DANN	Benign	0.14
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: rs28897693; hg19: chr17-41223119; COSMIC: COSV100525490; COSMIC: COSV100525490;