17-43097266-C-T

Position:

• chr17-43097266-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BP6_Very_Strong

The NM_007294.4(BRCA1):​c.571G>A​(p.Val191Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0001 in 1,613,640 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.00031 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000079 (0 hom.)
• Consequence: BRCA1 NM_007294.4 missense
• Clinical Significance: Benign reviewed by expert panel U:1 B:23
• Conservation: PhyloP100: 1.48

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.011903733).
• BP6: Variant 17-43097266-C-T is Benign according to our data. Variant chr17-43097266-C-T is described in ClinVar as [Benign]. Clinvar id is 37684.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43097266-C-T is described in Lovd as [Benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA1	NM_007294.4	c.571G>A	p.Val191Ile	missense_variant	8/23	ENST00000357654.9	NP_009225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9	c.571G>A	p.Val191Ile	missense_variant	8/23	1	NM_007294.4	ENSP00000350283	P4

Frequencies

GnomAD3 genomes AF: 0.000316 AC: 48 AN: 152070 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00615

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000302 AC: 76 AN: 251304 Hom.: 0 AF XY: 0.000272 AC XY: 37 AN XY: 135850

Gnomad AFR exome AF: 0.000431

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00348

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000787 AC: 115 AN: 1461452 Hom.: 0 Cov.: 30 AF XY: 0.0000839 AC XY: 61 AN XY: 727032

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00131

Gnomad4 SAS exome AF: 0.000128

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000234

Gnomad4 OTH exome AF: 0.000381

GnomAD4 genome AF: 0.000309 AC: 47 AN: 152188 Hom.: 0 Cov.: 32 AF XY: 0.000309 AC XY: 23 AN XY: 74400

Gnomad4 AFR AF: 0.000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00597

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000109 Hom.: 0

Bravo AF: 0.000246

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000296 AC: 36

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.0000546

EpiControl AF: 0.00

ClinVar

Significance: Benign

Submissions summary: Uncertain:1 Benign:23

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1 Uncertain:1 Benign:5

Benign, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Sep 16, 2008	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
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 = 0.000000157 -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	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 determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Uncertain significance, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA1)	May 29, 2002	- -
Likely benign, criteria provided, single submitter	clinical testing	Pathway Genomics	Oct 30, 2014	- -

not specified Benign:6

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	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Mar 20, 2017	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 16, 2013	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	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 15, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 28, 2016	Variant Summary: The variant of interest causes a missense change involving a non-conserved nucleotide with 3/4 in silico programs (SNPs&GO not captured here due to low reliability index) predict a "benign" outcome. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 36/121098 (1/3363), predominantly in the East Asian cohort, 29/8636 (1/297), which exceeds the predicted maximum expected allele frequency for a pathogenic BRCA1 variant of 1/1000. Therefore, suggesting that the variant of interest is a polymorphism found in population(s) of East Asian origin. The variant of interest has been reported in multiple affected individuals via publications and databases including multiple reported co-occurrences with a pathogenic BRCA1 variant, c.181T>G (p.Cys61Gly classified as pathogenic by LCA) and c.188T>A (p.L63X), and a pathogenic BRCA2 variant, c.9382C>T (p.R3128X). Functional studies show that the variant acts comparable to wild type function (Bouwman_2013, Lu_2015). In addition, multiple reputable clinical laboratories cite the variant with a classification of "likely benign/benign." Therefore, taking all available lines of evidence into consideration, the variant of interest is classified as Benign. -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2021	- -

Hereditary cancer-predisposing syndrome Benign:3

Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jan 22, 2016	- -
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. -
Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	Dec 09, 2020	- -

Hereditary breast ovarian cancer syndrome Benign:2

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 30, 2024	- -

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

Sep 06, 2022

- -

Familial cancer of breast;C2676676:Breast-ovarian cancer, familial, susceptibility to, 1;C3280442:Pancreatic cancer, susceptibility to, 4;C4554406:Fanconi anemia, complementation group S Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 10, 2022

- -

Malignant tumor of breast Benign:1

Benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The p.Val191Ile was identified in the literature in 9 of 1620 proband chromosomes (frequency: 0.006) from individuals with breast or ovarian cancer (Ang 2007, Chang 2001, Haffty 2009, Purnomosari 2007, Sng 2000, Thirthagiri 2008). The variant was also identified in dbSNP “With non-pathogenic allele” (ID: rs80357090), HGMD, LOVD, UMD (3X as a neutral variant), and the BIC database (10X with unknown clinical importance). This variant was reported with allelic frequencies of 0.001 and 0.0003 in the 1000 Genomes Project and Exome Variant Server ESP Project respectively, increasing the likelihood that this may be a low frequency benign variant in certain populations of origin. In addition, the variant was shown by Judkins (2005) to reside in trans with a known BRCA1 deleterious mutation (p.Leu63X), increasing the likelihood that the p.Val191Ile variant does not have clinical importance. Furthermore, Myriad classifies this variant as a “non-reportable polymorphism” (personal communication). Although the p.Val191 residue is conserved in mammals, computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM) do not suggest that the p.Val191Ile variant has a high likelihood of impact to the protein, and two in silico studies suggest that this variant is not pathogenic or of no clinical significance (Easton 2007, Lindor 2012). 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

Likely benign, no assertion criteria provided

literature only

Center for Precision Medicine, Meizhou People's Hospital

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.080	T
BayesDel_noAF	Uncertain	0.11
CADD	Benign	13
DANN	Benign	0.97
DEOGEN2	Benign	0.20	.;T;.;.;.;.;T;.;.;T;.;T;T
Eigen	Benign	-0.81
Eigen_PC	Benign	-0.83
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.76	T;T;T;T;T;T;T;T;T;T;T;T;T
MetaRNN	Benign	0.012	T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.17	D
MutationAssessor	Benign	1.6	L;L;L;L;.;L;.;.;.;.;.;.;.
MutationTaster	Benign	1.0	N;N;N;N;N;N;N;N;N;N;N;N;N;N
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.17	N;N;N;N;N;N;N;N;N;N;N;N;N
REVEL	Uncertain	0.53
Sift	Benign	0.057	T;D;D;D;D;D;D;D;D;D;D;D;T
Sift4G	Benign	0.25	T;T;T;T;T;T;.;T;T;T;.;T;.
Polyphen		0.0040, 0.63, 0.047	.;B;.;.;.;P;.;.;B;.;.;.;.
Vest4		0.10
MVP		0.70
MPC		0.068
ClinPred		0.0053	T
GERP RS		1.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.034
gMVP		0.28

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs80357090; hg19: chr17-41249283;