rs786203547

Positions:

• chr17-43063349-C-A
• chr17-43063349-C-G
• chr17-43063349-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM1 BP4 BP6

The NM_007294.4(BRCA1):​c.5177G>T​(p.Arg1726Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000754 in 1,458,812 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000075 (0 hom.)
• Consequence: BRCA1 NM_007294.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1 O:1
• Conservation: PhyloP100: 1.21

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 Uncertain_significance. Variant got 0 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
• BP4: Computational evidence support a benign effect (MetaRNN=0.26771137).
• BP6: Variant 17-43063349-C-A is Benign according to our data. Variant chr17-43063349-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 187201.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, not_provided=1, Uncertain_significance=3}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA1	NM_007294.4	c.5177G>T	p.Arg1726Ile	missense_variant	18/23	ENST00000357654.9	NP_009225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9	c.5177G>T	p.Arg1726Ile	missense_variant	18/23	1	NM_007294.4	ENSP00000350283	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000754 AC: 11 AN: 1458812 Hom.: 0 Cov.: 30 AF XY: 0.0000110 AC XY: 8 AN XY: 726024

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: 0.00000992

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

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

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	May 10, 2021	This alteration is classified as likely 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Sep 25, 2023	This missense variant replaces arginine with isoleucine at codon 1726 of the BRCA1 protein. Computational prediction tools and conservation analyses are inconclusive regarding the impact of this variant on the protein function. Functional studies have reported that this variant does not impact BRCA1 function in a haploid cell proliferation assay (PMID: 30209399) and in a homology-directed DNA repair assay (PMID: 30257991). This variant has been reported in one individual affected with breast cancer and the analysis of the tumor sample showed normal allelic balance indicating the absence of loss of heterozygosity (PMID: 35039532). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Quest Diagnostics Nichols Institute San Juan Capistrano

Dec 15, 2018

- -

Hereditary breast ovarian cancer syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 06, 2023

This sequence change replaces arginine, which is basic and polar, with isoleucine, which is neutral and non-polar, at codon 1726 of the BRCA1 protein (p.Arg1726Ile). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with personal and/or family history of breast and/or ovarian cancer (PMID: 21120943). ClinVar contains an entry for this variant (Variation ID: 187201). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 30209399) indicates that this missense variant is not expected to disrupt BRCA1 function. Experimental studies have shown that this missense change does not substantially affect BRCA1 function (PMID: 30209399, 30257991). 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. -

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

not provided, no classification provided

in vitro

Brotman Baty Institute, University of Washington

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.49
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.040
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.28	.;T;.;.;T;T;.;.;.;T
Eigen	Benign	-0.20
Eigen_PC	Benign	-0.19
FATHMM_MKL	Benign	0.71	D
LIST_S2	Uncertain	0.96	D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.37	D
MetaRNN	Benign	0.27	T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.34	T
MutationAssessor	Uncertain	2.0	.;M;.;.;.;.;.;.;.;.
MutationTaster	Benign	0.96	N;N;N;N;N;N;N;N;N;N;N;N;N;N
PrimateAI	Benign	0.37	T
PROVEAN	Pathogenic	-4.5	D;N;.;D;.;.;N;D;D;D
REVEL	Uncertain	0.52
Sift	Benign	0.062	T;D;.;T;.;.;D;T;D;D
Sift4G	Uncertain	0.053	T;T;T;D;T;T;T;T;.;.
Polyphen		0.093, 0.20, 0.72	.;B;.;.;.;B;.;.;.;P
Vest4		0.56
MVP		0.82
MPC		0.19
ClinPred		0.45	T
GERP RS		3.5
Varity_R		0.36
gMVP		0.64

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs786203547; hg19: chr17-41215366;