17-43082506-C-G

Position:

• chr17-43082506-C-G

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 2P and 10B. PM1 BP4_Moderate BP6_Very_Strong

The NM_007294.4(BRCA1):​c.4255G>C​(p.Glu1419Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000041 in 1,461,862 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★). Synonymous variant affecting the same amino acid position (i.e. E1419E) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: BRCA1 NM_007294.4 missense
• Clinical Significance: Benign reviewed by expert panel U:1 B:10
• Conservation: PhyloP100: 0.886

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 -8 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 15 uncertain in NM_007294.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.16162807).
• BP6: Variant 17-43082506-C-G is Benign according to our data. Variant chr17-43082506-C-G is described in ClinVar as [Benign]. Clinvar id is 55154.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43082506-C-G is described in Lovd as [Benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA1	NM_007294.4	c.4255G>C	p.Glu1419Gln	missense_variant	12/23	ENST00000357654.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA1	ENST00000357654.9	c.4255G>C	p.Glu1419Gln	missense_variant	12/23	1	NM_007294.4	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000410 AC: 6 AN: 1461862 Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3 AN XY: 727230

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000540

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Benign

Submissions summary: Uncertain:1 Benign:10

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1 Uncertain:1 Benign:3

Benign, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Oct 02, 2023	- -
Uncertain significance, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA1)	Nov 25, 2004	- -
Likely benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The p.Glu1419Gln variant has been identified in 2/114310 proband chromosomes of individuals with breast cancer and/or ovarian cancer; although, no control chromosomes were tested to establish the variant's frequency in the general population (Caux-Moncoutier 2011, Judkins 2005a, Lindor 2011, Millot 2012). The variant is listed in dbSNP database (ID#:rs80357309) as coming from a "clinical source" but no frequency information was provided, and so the prevalence of this variant in the population is not known. The p.Glu1419 residue is conserved in mammals, but computational analyses (PolyPhen, SIFT, AlignGVGD) do not suggest a high likelihood of impact to the protein. However, this information is not predictive enough to rule out pathogenicity. In addition, this variant is listed in the BIC (x1) database, as well as in the UMD mutation database to co-occur with a pathogenic mutation in BRCA2 c.3744_3747delTGAG (p.Ser1248ArgfsX10), increasing the likelihood that p.Glu1419Gln is benign. In summary, based on the above information, the p.Arg3370Arg variant is classified as predicted benign. -
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 = 0.000152 -

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 07, 2017	Variant summary: The BRCA1 c.4255G>C (p.Glu1419Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. 2/4 in silico tools predict a benign outcome for this variant (SNPs&GO not captured due to low reliability index). This variant is absent in 121396 control chromosomes. However, multiple publications cite the variant with a classification of "likely neutral." In addition, multiple reputable databases/clinical laboratories cite the variant with a classification of "benign/likely benign/uncertain significance." In addition, a poster abstract (IUBMB 2015) cites a functional study that showed the variant to act comparable to wild type functions for transcriptional activation ability and PALB2 interaction. One recent functional study (Woods_2016) showed preserved transcriptional activity and no deleterious effects on the BRCA1-PALB2 protein-protein interaction in the presence of this variant. Taken together, this variant is classified as likely benign. -
Likely benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Mar 13, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 20, 2019	This variant is associated with the following publications: (PMID: 22949387, 18951461, 21120943, 22753008, 17924331, 21990134) -

Hereditary cancer-predisposing syndrome Benign:2

Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 04, 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. -

Breast and/or ovarian cancer Benign:1

Likely benign, no assertion criteria provided

clinical testing

Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research

Aug 27, 2012

- -

Hereditary breast ovarian cancer syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 04, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Uncertain	0.069	T
BayesDel_noAF	Benign	-0.14
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.20	.;T;.;.;.;.;.;T;.;T
Eigen	Benign	0.020
Eigen_PC	Benign	0.079
FATHMM_MKL	Benign	0.72	D
LIST_S2	Uncertain	0.87	D;D;D;D;D;D;D;D;D;D
M_CAP	Benign	0.032	D
MetaRNN	Benign	0.16	T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.89	T
MutationAssessor	Uncertain	2.4	.;M;M;.;.;.;.;.;.;.
MutationTaster	Benign	0.67	D;D;D;D;D;D;D;D;D;D;D;D;N;N
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-1.1	N;N;N;N;N;N;N;N;N;N
REVEL	Benign	0.23
Sift	Uncertain	0.010	D;D;D;D;D;D;D;D;D;D
Sift4G	Benign	0.093	T;T;T;T;T;T;.;.;T;.
Polyphen		0.031, 1.0, 0.96	.;B;.;.;.;D;.;D;.;.
Vest4		0.32
MutPred		0.088		.;Loss of phosphorylation at S1423 (P = 0.2002);Loss of phosphorylation at S1423 (P = 0.2002);.;.;.;.;.;.;.;
MVP		0.67
MPC		0.41
ClinPred		0.93	D
GERP RS		4.5
Varity_R		0.30
gMVP		0.12

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: rs80357309; hg19: chr17-41234523;