17-43094838-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.693G>A(p.Thr231=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000109 in 1,612,652 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 (★★★). Synonymous variant affecting the same amino acid position (i.e. T231T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000092 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00011 (0 hom.)
• Consequence: BRCA1 NM_007294.4 synonymous
• Clinical Significance: Likely benign reviewed by expert panel U:5 B:13
• Conservation: PhyloP100: 0.293

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=-0.77).
• BP6: Variant 17-43094838-C-T is Benign according to our data. Variant chr17-43094838-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 55670.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43094838-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.293 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA1	NM_007294.4	c.693G>A	p.Thr231=	synonymous_variant	10/23	ENST00000357654.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA1	ENST00000357654.9	c.693G>A	p.Thr231=	synonymous_variant	10/23	1	NM_007294.4	P4

Frequencies

GnomAD3 genomes AF: 0.0000922 AC: 14 AN: 151828 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000657

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000948

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000177

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000686 AC: 17 AN: 247680 Hom.: 0 AF XY: 0.0000818 AC XY: 11 AN XY: 134408

Gnomad AFR exome AF: 0.0000650

Gnomad AMR exome AF: 0.0000584

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000931

Gnomad NFE exome AF: 0.000107

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000111 AC: 162 AN: 1460824 Hom.: 0 Cov.: 33 AF XY: 0.000111 AC XY: 81 AN XY: 726652

Gnomad4 AFR exome AF: 0.0000598

Gnomad4 AMR exome AF: 0.0000898

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000505

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000375

Gnomad4 NFE exome AF: 0.000130

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome AF: 0.0000922 AC: 14 AN: 151828 Hom.: 0 Cov.: 32 AF XY: 0.0000944 AC XY: 7 AN XY: 74150

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000657

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000948

Gnomad4 NFE AF: 0.000177

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000199 Hom.: 0

Bravo AF: 0.0000869

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:5 Benign:13

Revision: reviewed by expert panel

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:2 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Mar 23, 2022	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. -
Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Aug 23, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Dec 12, 2014	- -
Uncertain significance, no assertion criteria provided	clinical testing	True Health Diagnostics	Apr 06, 2018	- -

Breast-ovarian cancer, familial, susceptibility to, 1 Benign:4

Benign, criteria provided, single submitter	clinical testing	Michigan Medical Genetics Laboratories, University of Michigan	Apr 21, 2016	- -
Benign, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Mar 02, 2011	- -
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	- -

not specified Uncertain:1 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 31, 2020	Variant summary: BRCA1 c.693G>A results in a synonymous change. 4/4 computational tools predict no significant impact on normal splicing. However, multiple publications reports experimental evidence that this variant affects mRNA splicing, with the variant determining exon 11 skipping and a marked increase in amounts of the D(11) isoform (Brandao_2011, Raponi_2012, Tammaro_2014). The physiological consequences of this alteration are unknown since exon 11 skipping also occurs in normal breast tissue. The variant allele was found at a frequency of 6.9e-05 in 247680 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in BRCA1 causing Hereditary Breast and Ovarian Cancer (6.9e-05 vs 0.001), allowing no conclusion about variant significance. c.693G>A has been reported in the literature in sequencing studies of individuals affected with Hereditary Breast and Ovarian Cancer (example, Borg_2010, Brandao_2011, Song_2006, Momozawa_2018, Kraemer_2019). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. One recently published case control association study of Japanese individuals showed no association of this variant with breast cancer in males and females (Momozawa_2019). At-least one co-occurrence with another pathogenic variant has been reported in the UMD database (BRCA2 c.6082_6086delGAAGA, p.Glu2028LysfsX19), providing supporting evidence for a benign role. Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (benign, n=2; likely benign, n=2; VUS, n=4). Some of these submitters provide overlapping evidences utilized in the context of this evaluation. We have observed this variant at a frequency of 0.01% in our tested cohort and previously classified the variant as a VUS weighting the reported splicing evidence in our evaluation. However, in over two years since its initial evaluation, we have not observed any additional evidence supporting a pathogenic outcome and at-least one additional report supporting no association with breast cancer has been ascertained (Momozawa_2018). Based on the evidence outlined above, the variant was re-classified as likely benign. -
Likely benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 29, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Silent, not in splice site. ExAC: 1/5842 Finnish chromosomes; ClinVar: 2 labs B/LB, 2 labs VUS; 1 paper investigating constraint against synonymous substitutions in BRCA exon 11 -

not provided Uncertain:1 Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	May 11, 2023	Also known as 812G>A; This variant is associated with the following publications: (PMID: 24569164, 19370767, 26913838, 30287823, 25056543, 20104584, 21638052, 12890739, 16835750, 21702907, 28726806, 22615956, 31422574, 34597585, 32467295, 35402282, 35477782, 22817731, 29884841) -
Likely benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	May 17, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2023	BRCA1: BP4, BP7 -

Hereditary breast ovarian cancer syndrome Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	May 16, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 17, 2024	- -

Malignant tumor of breast Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The BRCA1 p.Thr231= variant was identified in 5 of 20638 proband chromosomes (frequency: 0.0002) from individuals or families with breast and ovarian cancer and was present in 5 of 47462 control chromosomes (frequency: 0.0001) from healthy individuals (Momozawa 2018, Borg 2010, Brandao 2011, Song 2006). The variant was also identified in dbSNP (ID: rs62625298) as "With Likely benign, Uncertain significance allele", ClinVar (classified as uncertain significance by GeneDx and 5 other submitters; as likely benign by ENIGMA expert panel in 2017 and Ambry Genetics; and as benign by Invitae and 2 other submitters), LOVD 3.0 and in UMD-LSDB (15 records, neutral classification). In UMD, the variant was reported as co-occurring with a pathogenic BRCA2 variant (c.6082_6086del, p.Glu2028Lysfs*19), increasing the likelihood that the p.Thr231= variant does not have clinical significance. It was identified in control databases in 22 of 274654 chromosomes at a frequency of 0.00008 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 1 of 23876 chromosomes (freq: 0.00004), Other in 1 of 6404 chromosomes (freq: 0.0002), Latino in 2 of 34158 chromosomes (freq: 0.00006), European in 14 of 125226 chromosomes (freq: 0.0001), and Finnish in 4 of 25642 chromosomes (freq: 0.0002), while it was not observed in the Ashkenazi Jewish, East Asian or South Asian populations. This variant was demonstrated to result in partial exon 11 skipping by RT-PCR and mini-gene assays, although the biological significance of the change in the ratio of splicing isoforms is unclear (Brandao 2011, Raponi 2012, Tammaro 2015). The p.Thr231= 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. However, 1 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) 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. This variant is classified as a variant of uncertain significance. -

BRCA1-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 26, 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	-0.77
Cadd	Benign	7.2
Dann	Benign	0.71
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs62625298; hg19: chr17-41246855;