rs1555597195

Positions:

• chr17-43106466-T-A
• chr17-43106466-T-C
• chr17-43106466-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_007294.4(BRCA1):​c.202A>T​(p.Ile68Leu) 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. Variant has been reported in ClinVar as not provided (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: BRCA1 NM_007294.4 missense
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: 1.85

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.41199064).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA1	NM_007294.4	c.202A>T	p.Ile68Leu	missense_variant	4/23	ENST00000357654.9	NP_009225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9	c.202A>T	p.Ile68Leu	missense_variant	4/23	1	NM_007294.4	ENSP00000350283	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 32

ClinVar

Significance: not provided

Submissions summary: Other:1

Revision: no classification provided

Submissions by phenotype

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	0.51
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.21	.;T;.;.;.;.;T;.;.;T;T;T;T;.
Eigen	Benign	0.047
Eigen_PC	Benign	0.047
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.82	T;T;T;T;T;T;T;T;T;T;T;T;T;T
M_CAP	Pathogenic	0.62	D
MetaRNN	Benign	0.41	T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.61	D
MutationAssessor	Uncertain	2.5	M;M;M;M;.;M;.;.;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;N;N;N;N;N;N;N;N;N;N
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-0.23	N;N;N;N;N;N;N;N;N;.;N;N;N;.
REVEL	Uncertain	0.60
Sift	Benign	0.12	T;D;D;T;D;T;T;D;D;.;D;D;T;.
Sift4G	Benign	0.22	T;T;T;T;T;T;.;D;T;.;D;D;.;.
Polyphen		0.90, 0.90, 0.24	.;P;.;.;.;P;.;.;B;.;.;.;.;.
Vest4		0.55
MutPred		0.42		Gain of disorder (P = 0.0711);Gain of disorder (P = 0.0711);Gain of disorder (P = 0.0711);Gain of disorder (P = 0.0711);.;Gain of disorder (P = 0.0711);Gain of disorder (P = 0.0711);.;Gain of disorder (P = 0.0711);Gain of disorder (P = 0.0711);Gain of disorder (P = 0.0711);Gain of disorder (P = 0.0711);Gain of disorder (P = 0.0711);.;
MVP		0.92
MPC		0.18
ClinPred		0.83	D
GERP RS		3.6
Varity_R		0.68
gMVP		0.44

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs1555597195; hg19: chr17-41258483;