17-43094075-A-G

Position:

• chr17-43094075-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_007294.4(BRCA1):​c.1456T>C​(p.Phe486Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000348 in 1,614,110 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.00039 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00034 (7 hom.)
• Consequence: BRCA1 NM_007294.4 missense
• Clinical Significance: Benign reviewed by expert panel U:3 B:33 O:1
• Conservation: PhyloP100: -0.927

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.06601533).
• BP6: Variant 17-43094075-A-G is Benign according to our data. Variant chr17-43094075-A-G is described in ClinVar as [Benign]. Clinvar id is 54258.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43094075-A-G is described in Lovd as [Benign]. Variant chr17-43094075-A-G is described in Lovd as [Likely_benign]. Variant chr17-43094075-A-G is described in Lovd as [Pathogenic].
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.000344 (503/1461822) while in subpopulation MID AF= 0.0182 (105/5768). AF 95% confidence interval is 0.0154. There are 7 homozygotes in gnomad4_exome. There are 267 alleles in male gnomad4_exome subpopulation. Median coverage is 34. 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.1456T>C	p.Phe486Leu	missense_variant	10/23	ENST00000357654.9	NP_009225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9	c.1456T>C	p.Phe486Leu	missense_variant	10/23	1	NM_007294.4	ENSP00000350283.3

Frequencies

GnomAD3 genomes AF: 0.000388 AC: 59 AN: 152170 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000193

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: 0.00143

GnomAD3 exomes AF: 0.000279 AC: 70 AN: 251292 Hom.: 0 AF XY: 0.000368 AC XY: 50 AN XY: 135810

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000359

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000370

Gnomad OTH exome AF: 0.000653

GnomAD4 exome AF: 0.000344 AC: 503 AN: 1461822 Hom.: 7 Cov.: 34 AF XY: 0.000367 AC XY: 267 AN XY: 727206

Gnomad4 AFR exome AF: 0.000329

Gnomad4 AMR exome AF: 0.000246

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000348

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000269

Gnomad4 OTH exome AF: 0.000745

GnomAD4 genome AF: 0.000387 AC: 59 AN: 152288 Hom.: 1 Cov.: 32 AF XY: 0.000430 AC XY: 32 AN XY: 74458

Gnomad4 AFR AF: 0.000192

Gnomad4 AMR AF: 0.000916

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000353

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000543 Hom.: 1

Bravo AF: 0.000434

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: 0.000296 AC: 36

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000327

EpiControl AF: 0.000711

ClinVar

Significance: Benign

Submissions summary: Uncertain:3 Benign:33 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1 Uncertain:2 Benign:9

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 = 0.00000000000186 -
Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Genomic Research Center, Shahid Beheshti University of Medical Sciences	May 03, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Sep 01, 2015	- -
Uncertain significance, 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. 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. -
Benign, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Feb 25, 2011	- -
Benign, criteria provided, single submitter	clinical testing	Michigan Medical Genetics Laboratories, University of Michigan	Apr 21, 2016	- -
Likely benign, criteria provided, single submitter	literature only	Counsyl	Mar 31, 2014	- -
Uncertain significance, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA1)	May 29, 2002	- -
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	- -

not specified Benign:10 Other:1

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. -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jan 19, 2022	- -
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, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 21, 2018	Variant summary: BRCA1 c.1456T>C (p.Phe486Leu) results in a non-conservative amino acid change located in the BRCA1, serine-rich domain of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00028 in 278056 control chromosomes. This frequency is not higher than expected for a pathogenic variant in BRCA1 causing Hereditary Breast and Ovarian Cancer (0.00028 vs 0.001), allowing no conclusion about variant significance. This variant has been reported in cis with Y179C and N550H in most patients and has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer; however a possible lack of cosegregation in at least two families has been reported (Caligo_2009; Mahfoudh_2012). Co-occurrences with other pathogenic variants have been reported (BRCA1 p.W321X; BRCA2 p.S1970X; BRCA2 p.E2028KfsX19), providing supporting evidence for a benign role. Several publications report experimental evidence evaluating an impact on protein function, including homologous repair, protein-protein interactions, and single stand annealing assays, all of which showed no damaging effect caused by the variant (Caligo_2009; Anantha_2017). Ten clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 with conflicting assessments; however, the majority of labs classified the variant in the benign spectrum (LB/B = 8; VUS = 2). Based on the evidence outlined above, the variant was classified as benign. -
Benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	Abkevich_2004_ Augello_2006 Lindor_2011 Caliqo_2008 Caux-Moncoutier_2009 Diez_2003 Judkins_2005a Spurdle_2008 Tavtigian_2006 -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -

not provided Benign:6

Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	May 16, 2017	- -
Likely benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Aug 02, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Sep 03, 2022	- -
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	- -

Hereditary cancer-predisposing syndrome Benign:4

Benign, criteria provided, single submitter	curation	Sema4, Sema4	Jun 25, 2020	- -
Likely benign, no assertion criteria provided	clinical testing	True Health Diagnostics	Apr 05, 2018	- -
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	clinical testing	Color Diagnostics, LLC DBA Color Health	Dec 15, 2014	- -

Hereditary breast ovarian cancer syndrome Uncertain:1 Benign:2

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

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

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.36
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.13
CADD	Benign	0.019
DANN	Benign	0.38
DEOGEN2	Benign	0.24	T;.;.;.;T;T;.
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.025	N
LIST_S2	Benign	0.73	T;T;T;T;T;T;T
M_CAP	Uncertain	0.21	D
MetaRNN	Benign	0.066	T;T;T;T;T;T;T
MetaSVM	Benign	-0.67	T
MutationAssessor	Uncertain	2.0	M;M;.;.;.;.;.
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-0.96	N;N;N;N;.;N;N
REVEL	Uncertain	0.57
Sift	Benign	0.42	T;T;T;T;.;T;T
Sift4G	Benign	0.70	T;T;T;T;.;T;.
Polyphen		0.0	B;.;.;B;.;.;.
Vest4		0.23
MutPred		0.48		Loss of helix (P = 0.0093);Loss of helix (P = 0.0093);.;Loss of helix (P = 0.0093);.;Loss of helix (P = 0.0093);.;
MVP		0.56
MPC		0.095
ClinPred		0.0039	T
GERP RS		-3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.019
gMVP		0.040

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: rs55906931; hg19: chr17-41246092; COSMIC: COSV58790881; COSMIC: COSV58790881;