17-43067638-C-T

Position:

• chr17-43067638-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 4P and 8B. PM1 PM2 BP6_Very_Strong

The NM_007294.4(BRCA1):​c.5044G>A​(p.Glu1682Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Benign (★★★).

• Frequency: Genomes: not found (cov: 30)
• Consequence: BRCA1 NM_007294.4 missense
• Clinical Significance: Benign reviewed by expert panel U:3 B:3 O:1
• Conservation: PhyloP100: 2.22

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 Likely_benign. Variant got -4 ACMG points.

• PM1: In a domain BRCT 1 (size 94) in uniprot entity BRCA1_HUMAN there are 74 pathogenic changes around while only 17 benign (81%) in NM_007294.4
• PM2: Very rare variant in population databases, with high coverage
• BP6: Variant 17-43067638-C-T is Benign according to our data. Variant chr17-43067638-C-T is described in ClinVar as [Benign]. Clinvar id is 55361.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43067638-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.5044G>A	p.Glu1682Lys	missense_variant	16/23	ENST00000357654.9	NP_009225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9	c.5044G>A	p.Glu1682Lys	missense_variant	16/23	1	NM_007294.4	ENSP00000350283.3

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 30

ClinVar

Significance: Benign

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

Revision: reviewed by expert panel

Submissions by phenotype

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

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 = 0.0000976 -
Uncertain significance, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA1)	Jun 20, 2002	- -
not provided, no classification provided	in vitro	Brotman Baty Institute, University of Washington	-	- -

not specified Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 30, 2023	Variant summary: BRCA1 c.5044G>A (p.Glu1682Lys) results in a conservative amino acid change in BRCT domain (IPR001357) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 251368 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.5044G>A has been reported in the literature in unspecified individual(s) who underwent clinical BRCA1 screening, without strong evidence for causality (example, Judkins_2005). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. Co-occurrence with at-least one pathogenic variant, at a homozygous state has been reported (BRCA1 c.3048_3052dup, p.Asn1018fs), providing supporting evidence for a benign role (described as c.3171ins5 by Judkins_2005). At least one publication reports experimental evidence evaluating an impact on protein function. Two of which showed no damaging effect of this variant on protein levels, colony formation, protease sensitivity, binding activity, transcription activity and structural stability in yeast or mammalian cells (Lee_2010, Thouvenot_2016). Meanwhile, a functional study via a high-throughput, genome editing, haploid cell survival assay evaluated this variant loss-of-function based on a decrease in mRNA expression (Findlay_2018). The following publications have been ascertained in the context of this evaluation (PMID: 30209399, 16267036, 20516115, 27272900). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 (Benign, n=1, Likely benign, n=2, VUS, n=1). Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 22, 2017	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. -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 15, 2024

The p.E1682K variant (also known as c.5044G>A), located in coding exon 15 of the BRCA1 gene, results from a G to A substitution at nucleotide position 5044. The glutamic acid at codon 1682 is replaced by lysine, an amino acid with similar properties. This alteration has been reported to be found in trans with another BRCA1 pathogenic mutation (Judkins T et al. Cancer Res, 2005 Nov;65:10096-103). Multifactorial analyses determined that this alteration to be benign (Easton DF et al. Am J Hum Genet, 2007 Nov;81:873-83; Lindor NM et al. Hum Mutat, 2012 Jan;33:8-21). One protein functional study determined that this alteration was functional in protease sensitivity, peptide binding, peptide binding specificity, and transcriptional activity assays (Lee MS et al. Cancer Res, 2010 Jun;70:4880-90). One functional study found that this nucleotide substitution is non-functional in a high-throughput, genome editing, haploid cell survival assay and was measured to have a decrease in mRNA expression (Findlay GM et al. Nature, 2018 10;562:217-222). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site; however, direct evidence is insufficient at this time (Ambry internal data). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is conflicting at this time, the clinical significance of this alteration remains unclear. -

Hereditary breast ovarian cancer syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Mar 12, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.060
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.11	.;T;.;.;T;.;.;.;T;.
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.91	D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.61	D
MetaRNN	Uncertain	0.59	D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.73	D
MutationAssessor	Benign	1.9	.;L;.;.;.;.;.;.;.;.
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-2.3	N;N;.;N;.;N;N;D;N;D
REVEL	Uncertain	0.62
Sift	Benign	0.15	T;D;.;T;.;D;T;D;D;D
Sift4G	Benign	0.099	T;D;D;T;D;D;T;.;.;D
Polyphen		0.10, 1.0	.;B;.;.;.;.;.;.;D;.
Vest4		0.56
MVP		0.85
MPC		0.096
ClinPred		0.81	D
GERP RS		5.2
Varity_R		0.71
gMVP		0.50

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.57		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.57		Position offset: -30

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs80356958; hg19: chr17-41219655; COSMIC: COSV58790756;