rs80357429

Positions:

• chr17-43071127-G-A
• chr17-43071127-G-C
• chr17-43071127-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The ENST00000357654.9(BRCA1):​c.4787C>T​(p.Ser1596Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S1596A) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: BRCA1 ENST00000357654.9 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 4.66

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA1	NM_007294.4	c.4787C>T	p.Ser1596Leu	missense_variant	15/23	ENST00000357654.9	NP_009225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9	c.4787C>T	p.Ser1596Leu	missense_variant	15/23	1	NM_007294.4	ENSP00000350283	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

Submissions by phenotype

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

Uncertain significance, no assertion criteria provided

clinical testing

Breast Cancer Information Core (BIC) (BRCA1)

-

- -

Breast neoplasm Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Laboratory of Molecular Diagnosis of Cancer, West China Hospital, Sichuan University

Nov 01, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.16
CADD	Benign	18
DANN	Uncertain	1.0
DEOGEN2	Benign	0.22	.;T;.;.;T;.;.;.;T;.
Eigen	Benign	0.14
Eigen_PC	Benign	0.041
FATHMM_MKL	Benign	0.43	N
LIST_S2	Uncertain	0.92	D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.54	D
MetaRNN	Uncertain	0.66	D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.23	D
MutationAssessor	Benign	1.9	.;L;.;.;.;.;.;.;.;.
MutationTaster	Benign	0.59	D;D;D;D;D;D;D;D;D;D;N;N;N;N
PrimateAI	Benign	0.37	T
PROVEAN	Uncertain	-3.0	D;N;N;D;.;N;D;D;N;D
REVEL	Pathogenic	0.65
Sift	Uncertain	0.0020	D;D;T;D;.;D;D;D;D;D
Sift4G	Benign	0.12	T;D;D;T;D;D;T;.;.;D
Polyphen		0.031, 1.0	.;B;.;.;.;.;.;.;D;.
Vest4		0.46
MVP		0.88
MPC		0.11
ClinPred		0.89	D
GERP RS		4.4
Varity_R		0.095
gMVP		0.27

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: rs80357429; hg19: chr17-41223144;