17-43045754-A-G

Position:

• chr17-43045754-A-G

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1 PM2 PP3_Moderate PP5_Very_Strong

The NM_007294.4(BRCA1):​c.5516T>C​(p.Leu1839Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: BRCA1 NM_007294.4 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:6 U:3 O:1
• Conservation: PhyloP100: 4.98

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 Pathogenic. Variant got 14 ACMG points.

• PM1: In a helix (size 9) in uniprot entity BRCA1_HUMAN there are 8 pathogenic changes around while only 1 benign (89%) in NM_007294.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.909
• PP5: Variant 17-43045754-A-G is Pathogenic according to our data. Variant chr17-43045754-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 91656.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA1	NM_007294.4	c.5516T>C	p.Leu1839Ser	missense_variant	23/23	ENST00000357654.9	NP_009225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9	c.5516T>C	p.Leu1839Ser	missense_variant	23/23	1	NM_007294.4	ENSP00000350283.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6 Uncertain:3 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:4 Uncertain:2 Other:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Feb 02, 2024	Criteria applied: PS3,PP4_STR,PM2_SUP -
not provided, no classification provided	in vitro	Brotman Baty Institute, University of Washington	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Apr 10, 2012	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 03, 2023	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Jun 28, 2023	This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 30209399, 35196514]. -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	May 31, 2018	- -
Pathogenic, reviewed by expert panel	curation	Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	Jun 18, 2019	IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 5 based on posterior probability = 0.999548 -

Hereditary cancer-predisposing syndrome Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 27, 2023	The p.L1839S variant (also known as c.5516T>C), located in coding exon 22 of the BRCA1 gene, results from a T to C substitution at nucleotide position 5516. The leucine at codon 1839 is replaced by serine, an amino acid with dissimilar properties. This alteration was identified in a cohort of German patients considered to be at increased risk for HBOC syndrome (Meisel C et al. Arch Gynecol Obstet, 2017 May;295:1227-1238). One functional study found that this nucleotide substitution is non-functional in a high-throughput, genome editing, haploid cell survival assay (Findlay GM et al. Nature, 2018 10;562:217-222). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Oct 24, 2023	This missense variant replaces leucine with serine at codon 1839 of the BRCA1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have reported that this variant impacts BRCA1 function in a homology-directed DNA repair assay and in a haploid cell proliferation assay (PMID: 30209399, 35196514). This variant has been reported in one individual each affected with ovarian and breast cancer (PMID: 33078592, 33875706) and in a suspected hereditary breast and ovarian cancer family (PMID: 28324225). A multifactorial analysis has reported likelihood ratios for pathogenicity based on segregation and tumor pathology of 21.9613 and 51.8951, respectively (PMID: 31131967). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -

Hereditary breast ovarian cancer syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 14, 2025

This sequence change replaces leucine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 1839 of the BRCA1 protein (p.Leu1839Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of BRCA1-related conditions (PMID: 33078592). ClinVar contains an entry for this variant (Variation ID: 91656). Invitae Evidence Modeling incorporating data from in vitro experimental studies (PMID: 30209399) indicates that this missense variant is expected to disrupt BRCA1 function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects BRCA1 function (PMID: 35196514). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.41
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.40	.;T;.;T;T;T;.;.
Eigen	Pathogenic	0.71
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.94	D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.79	D
MetaRNN	Pathogenic	0.91	D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.45	D
MutationAssessor	Uncertain	2.3	.;M;.;.;.;.;.;.
PrimateAI	Benign	0.46	T
PROVEAN	Pathogenic	-4.6	D;N;.;.;.;.;N;D
REVEL	Pathogenic	0.73
Sift	Pathogenic	0.0	D;D;.;.;.;.;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D;D;D;D;D
Polyphen		1.0	.;D;.;.;.;D;.;.
Vest4		0.87
MVP		0.95
MPC		0.53
ClinPred		0.99	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.72
gMVP		0.67

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: rs398122702; hg19: chr17-41197771;