rs397509197

Positions:

• chr17-43071137-T-A
• chr17-43071137-T-C
• chr17-43071137-T-G

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BP6

The NM_007294.4(BRCA1):​c.4777A>T​(p.Ile1593Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I1593V) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: BRCA1 NM_007294.4 missense
• Clinical Significance: Likely benign no assertion criteria provided B:1 O:1
• Conservation: PhyloP100: -1.51

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 -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12551612).
• BP6: Variant 17-43071137-T-A is Benign according to our data. Variant chr17-43071137-T-A is described in ClinVar as [Likely_benign]. Clinvar id is 55286.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA1	NM_007294.4	c.4777A>T	p.Ile1593Leu	missense_variant	15/23	ENST00000357654.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA1	ENST00000357654.9	c.4777A>T	p.Ile1593Leu	missense_variant	15/23	1	NM_007294.4	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely benign

Submissions summary: Benign:1 Other:1

Revision: no assertion criteria provided

Submissions by phenotype

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

Likely benign, no assertion criteria provided

clinical testing

Department of Medical and Surgical Sciences, University of Bologna

Sep 01, 2023

PM2(Supporting)+BP1(Strong) according to ACMG/AMP classification guidelines specified for BRCA1 & BRCA2 (Classification Criteria V1.0.0 2023-09-08 - https://cspec.genome.network/cspec/ui/svi/affiliation/50087) (PMID: 38160042) -

Familial cancer of breast Other:1

not provided, no classification provided

literature only

ClinVar Staff, National Center for Biotechnology Information (NCBI)

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Pathogenic	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Benign	0.053
DANN	Benign	0.56
DEOGEN2	Benign	0.078	.;T;.;.;T;.;.;.;T;.
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.012	N
LIST_S2	Benign	0.69	T;T;T;T;T;T;T;T;T;T
M_CAP	Uncertain	0.098	D
MetaRNN	Benign	0.13	T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.78	T
MutationAssessor	Benign	1.1	.;L;.;.;.;.;.;.;.;.
MutationTaster	Benign	1.0	N;N;N;N;N;N;N;N;N;N;N;N;N;N
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.21	N;N;.;N;.;N;N;N;N;N
REVEL	Uncertain	0.55
Sift	Benign	0.42	T;T;.;T;.;T;T;T;T;T
Sift4G	Benign	0.76	T;T;T;T;T;T;T;.;.;T
Polyphen		0.025, 0.0	.;B;.;.;.;.;.;.;B;.
Vest4		0.71
MVP		0.21
MPC		0.082
ClinPred		0.063	T
GERP RS		-2.9
Varity_R		0.034
gMVP		0.11

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: rs397509197; hg19: chr17-41223154;