chr17-43099786-T-C

Position:

• chr17-43099786-T-C

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_007294.4(BRCA1):​c.536A>G​(p.Tyr179Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000337 in 1,608,112 control chromosomes in the GnomAD database, including 8 homozygotes. Variant has been reported in ClinVar as Benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.00035 (1 hom., cov: 31)
  • Exomes 𝑓: 0.00034 (7 hom.)
• Consequence: BRCA1 NM_007294.4 missense
• Clinical Significance: Benign reviewed by expert panel U:2 B:36
• Conservation: PhyloP100: 3.36

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 -16 ACMG points.

• BP6: Variant 17-43099786-T-C is Benign according to our data. Variant chr17-43099786-T-C is described in ClinVar as [Benign]. Clinvar id is 37661.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43099786-T-C is described in Lovd as [Benign]. Variant chr17-43099786-T-C is described in Lovd as [Likely_benign]. Variant chr17-43099786-T-C is described in Lovd as [Pathogenic].
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.000336 (489/1455778) while in subpopulation MID AF= 0.0181 (104/5754). AF 95% confidence interval is 0.0153. There are 7 homozygotes in gnomad4_exome. There are 256 alleles in male gnomad4_exome subpopulation. Median coverage is 30. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 7 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA1	NM_007294.4	c.536A>G	p.Tyr179Cys	missense_variant	7/23	ENST00000357654.9	NP_009225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9	c.536A>G	p.Tyr179Cys	missense_variant	7/23	1	NM_007294.4	ENSP00000350283.3

Frequencies

GnomAD3 genomes AF: 0.000348 AC: 53 AN: 152216 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000917

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.000353

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.000258 AC: 65 AN: 251464 Hom.: 0 AF XY: 0.000338 AC XY: 46 AN XY: 135898

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000261

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000369

Gnomad OTH exome AF: 0.000652

GnomAD4 exome AF: 0.000336 AC: 489 AN: 1455778 Hom.: 7 Cov.: 30 AF XY: 0.000353 AC XY: 256 AN XY: 724678

Gnomad4 AFR exome AF: 0.0000901

Gnomad4 AMR exome AF: 0.000246

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000313

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000269

Gnomad4 OTH exome AF: 0.000731

GnomAD4 genome AF: 0.000348 AC: 53 AN: 152334 Hom.: 1 Cov.: 31 AF XY: 0.000403 AC XY: 30 AN XY: 74490

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.000915

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000353

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000521 Hom.: 0

Bravo AF: 0.000400

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000272 AC: 33

EpiCase AF: 0.000327

EpiControl AF: 0.000711

ClinVar

Significance: Benign

Submissions summary: Uncertain:2 Benign:36

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1 Uncertain:1 Benign:11

Benign, criteria provided, single submitter	clinical testing	Michigan Medical Genetics Laboratories, University of Michigan	Apr 21, 2016	- -
Benign, reviewed by expert panel	curation	Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	Aug 10, 2015	IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 1 based on posterior probability = 0.00000000000173 -
Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Likely benign, criteria provided, single submitter	literature only	Counsyl	Apr 07, 2014	- -
Uncertain significance, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA1)	May 29, 2002	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Nov 19, 2018	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 rule this variant out of causing disease. Therefore, this variant is classified as benign. -
Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Sep 01, 2015	- -
Benign, no assertion criteria provided	clinical testing	BRCAlab, Lund University	Mar 02, 2020	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
Benign, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	May 01, 2012	- -
Likely benign, criteria provided, single submitter	clinical testing	Genomic Research Center, Shahid Beheshti University of Medical Sciences	May 03, 2020	- -

not specified Benign:10

Benign, no assertion criteria provided	research	Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	Jan 31, 2014	- -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jan 19, 2022	- -
Benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 23, 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: ClinVar: 6 B/LB, including expert panel -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 22, 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. -
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	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 04, 2015	- -
Benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

not provided Benign:6

Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	May 16, 2017	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	BRCA1: BP1, BS3:Moderate, BS1 -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 18, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Sep 03, 2022	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Aug 01, 2017	- -

Hereditary cancer-predisposing syndrome Benign:4

Likely benign, no assertion criteria provided	clinical testing	True Health Diagnostics	Apr 05, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Dec 15, 2014	- -
Benign, criteria provided, single submitter	curation	Sema4, Sema4	Jun 25, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 18, 2014	This alteration is classified as 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 Uncertain:1 Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Sep 02, 2015	- -
Likely benign, no assertion criteria provided	clinical testing	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	Apr 07, 2022	- -

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

Feb 22, 2023

- -

BRCA1-related cancer predisposition Benign:1

Likely benign, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Sep 27, 2024

- -

Malignant tumor of breast Benign:1

Benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The p.Tyr179Cys variant has been identified in 11 of 5342 proband chromosomes (frequency 0.002) in individuals with breast or ovarian cancers (Akbari 2011, Augello 2006, Caligo 2008, Diez 2003, Jalkh 2012, Russo 2007, Solano 2012) and was absent in 400 control chromosomes from these studies. Myriad reports this variant as a polymorphism, and Exome Server Project reports a frequency of 0.0003 in European American alleles, and 0.0002 in African American alleles. This variant has been also been reported in dbSNP (ID: rs56187033) “with non-pathogenic allele”, in the BIC database 54X as a variant of unknown clinical importance, and in UMD 27X as a neutral variant which co-occurred with pathogenic mutations in BRCA1 or BRCA2 four times (BRCA1 c.2043dup (p.Asn682X), BRCA1 c.191G>A (p.Cys64Tyr), BRCA2 c.6082_6086delGAAGA (p.Glu2028LysfsX19), BRCA2 c.5909C>A (p.Ser1970X)). The p.Tyr179 residue is conserved in mammals; however, computational analyses (PolyPhen2, SIFT, AlignGVGD) provide inconsistent predictions regarding the impact to the protein, and this information is not very predictive of pathogenicity. Functional studies on the p.Tyr179Cys variant have suggested that it may have a deleterious effect on BRCA1 function, in assays evaluating its effect in homologous repair (Caligo 2008, Di Cecco 2009), non-homologous end-joining (Guidugli 2011), interaction of BRCA1 with Filamin A (Velkova 2010), and accumulation of BRCA1 at double-strand breaks (Wei 2008). Many studies have identified the p.Tyr179Cys variant co-occurring with two other BRCA1 variants, p.Phe486Lys and p.Asn550His, in individuals with breast or ovarian cancers (Augello 2006, Caligo 2008, Diez 2003, Jalkh 2012), suggesting that together they constitute a rare haplotype (Tavtigian 2006). Furthermore, Augello (2006) identified these three mutations in three members of one family indicating that they exist in cis, and suggests that the presence of the three variants might produce an effect on the conformation of the protein and, consequently, on its function. In summary, this variant meets our laboratory's criteria to be classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.52
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.32	.;T;.;.;.;.;.;T;.;T;.;T;T;.;T;T
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.88	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.88	D
MetaRNN	Uncertain	0.62	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.5	M;M;M;M;.;M;.;.;.;.;.;.;.;.;.;.
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-0.47	N;N;N;N;N;N;N;D;N;D;N;.;N;N;N;D
REVEL	Pathogenic	0.75
Sift	Uncertain	0.0010	D;D;D;D;D;D;D;D;D;D;D;.;D;D;D;D
Sift4G	Benign	0.085	T;D;D;T;D;T;.;.;T;.;D;.;D;.;D;.
Polyphen		1.0, 1.0	.;D;.;.;.;D;.;D;.;.;D;.;.;.;.;.
Vest4		0.72
MVP		0.96
MPC		0.47
ClinPred		0.12	T
GERP RS		5.2
Varity_R		0.30
gMVP		0.33

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: rs56187033; hg19: chr17-41251803; COSMIC: COSV58790895; COSMIC: COSV58790895;