rs80357002

chr17-43071149-G-Achr17-43071149-G-C

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_Moderate BP6

The NM_007294.4(BRCA1):c.4765C>T(p.Arg1589Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000013 in 1,461,884 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1589H) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000013 (0 hom.)
• Consequence: BRCA1 NM_007294.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:8
• Conservation: PhyloP100: 0.345

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 Likely_benign. Variant got -3 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.23940855).
• BP6: Variant 17-43071149-G-A is Benign according to our data. Variant chr17-43071149-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 55283.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=6, Uncertain_significance=3}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA1	NM_007294.4	c.4765C>T	p.Arg1589Cys	missense_variant	15/23	ENST00000357654.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA1	ENST00000357654.9	c.4765C>T	p.Arg1589Cys	missense_variant	15/23	1	NM_007294.4	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000119 AC: 3 AN: 251386 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135858

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000130 AC: 19 AN: 1461884 Hom.: 0 Cov.: 33 AF XY: 0.00000963 AC XY: 7 AN XY: 727242

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000812

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000899

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:8

Revision: criteria provided, conflicting classifications

Submissions by phenotype

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

Uncertain significance, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA1)	Feb 20, 2004	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Molecular Endocrinology Laboratory, Christian Medical College	-	- -
Likely benign, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Oct 23, 2023	- -
Benign, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Aug 10, 2012	- -

Hereditary cancer-predisposing syndrome Benign:4

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 26, 2018	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. -
Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	Mar 28, 2021	- -
Likely benign, no assertion criteria provided	clinical testing	True Health Diagnostics	May 30, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Nov 21, 2016	- -

not specified Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Apr 28, 2020	DNA sequence analysis of the BRCA1 gene demonstrated a sequence change, c.4765C>T, in exon 15 that results in an amino acid change, p.Arg1589Cys. This sequence change has been described in the gnomAD database in three individuals (dbSNP rs80357002). The p.Arg1589Cys change has been described in one individual from a hereditary breast and ovarian cancer family (PMID: 16267036). The p.Arg1589Cys change affects a poorly conserved amino acid residue located in a domain of the BRCA1 protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Arg1589Cys substitution. Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Arg1589Cys change remains unknown at this time. -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 19, 2016	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 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Aug 28, 2016

Variant summary: The BRCA1 c.4765C>T (p.Arg1589Cys) variant causes a missense change involving a non-conserved nucleotide with 2/4 in silico tools (SNPs&GO not captured due to low reliability index) predict a benign outcome. This variant is not located in any known domain/repeats, however lies in flanking region of BRCA2 repeat regions (InterPro). The variant of interest was observed in the large and broad control population from ExAC with an allele frequency of 2/121346 (1/60673), which does not exceed the estimated maximal expected allele frequency for a pathogenic BRCA1 variant of 1/1000. The variant has been reported in HBOC families, however with limited information (i.e. no data about co-occurrence and cosegregation provided). However, a reputable database (BIC) cites the variant to co-occur with a pathogenic BRCA2 variant (c.1929delG), suggesting that it was not a primary cause of disease in the patient. In addition, this variant had similar transcription activation activity in comparison to wildtype (Woods_2016). Multiple reputable databases/clinical laboratories cite the variant as "uncertain significance" (n=2) or "likely benign/benign" (n=2). Another variant at the same residue (p.Arg1589His) has also been reported in UMD five times, one of which also carried a deleterious variant in BRCA2 (c.317-2A>G) and results in transcription activation similar to wildtype (Woods_2016). Therefore, taken all available information into consideration, the variant of interest has been classified as a variant of uncertain significance (VUS)-possibly benign/possible normal variant until additional information becomes available. -

Hereditary breast ovarian cancer syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	0.030
Cadd	Benign	13
Dann	Uncertain	1.0
Eigen	Benign	-0.79
Eigen_PC	Benign	-0.79
FATHMM_MKL	Benign	0.049	N
LIST_S2	Benign	0.85	D;D;D;T;D;D;D;D;D;D
M_CAP	Pathogenic	0.48	D
MetaRNN	Benign	0.24	T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.54	T
MutationTaster	Benign	1.0	N;N;N;N;N;N;N;N;N;N;N;N;N;N
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-1.7	N;N;.;N;.;N;N;N;N;N
REVEL	Uncertain	0.53
Sift	Uncertain	0.0080	D;D;.;D;.;D;D;D;D;D
Sift4G	Uncertain	0.018	D;D;D;D;T;D;D;.;.;D
Polyphen		0.096, 0.27	.;B;.;.;.;.;.;.;B;.
Vest4		0.18
MVP		0.63
MPC		0.20
ClinPred		0.18	T
GERP RS		2.5
Varity_R		0.061
gMVP		0.17

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: rs80357002; hg19: chr17-41223166; COSMIC: COSV58792764; COSMIC: COSV58792764;