rs1555596670

chr17-43104899-A-Cchr17-43104899-A-Gchr17-43104899-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1 PM2 BP4

The NM_007294.4(BRCA1):c.270T>G(p.Ile90Met) 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I90F) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: BRCA1 NM_007294.4 missense
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: 1.99

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 3 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 5 benign, 17 uncertain in NM_007294.4
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.37634718).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA1	NM_007294.4	c.270T>G	p.Ile90Met	missense_variant	5/23	ENST00000357654.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA1	ENST00000357654.9	c.270T>G	p.Ile90Met	missense_variant	5/23	1	NM_007294.4	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

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

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
Cadd	Benign	22
Dann	Uncertain	1.0
Eigen	Uncertain	0.24
Eigen_PC	Benign	0.21
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.82	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
M_CAP	Pathogenic	0.30	D
MetaRNN	Benign	0.38	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.20	D
MutationAssessor	Uncertain	2.1	M;M;M;M;.;M;.;.;.;.;.;.;.;.;.;.;.;.
MutationTaster	Benign	0.67	D;D;D;D;D;D;N;N;N;N;N;N;N;N
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-0.14	N;N;N;N;N;N;N;N;N;N;N;.;N;N;N;D;N;.
REVEL	Uncertain	0.57
Sift	Uncertain	0.020	D;T;T;T;T;T;T;T;T;T;T;.;T;T;T;T;T;.
Sift4G	Uncertain	0.045	D;T;T;D;T;D;.;.;D;.;T;.;T;.;T;.;.;.
Polyphen		0.99, 0.99, 0.93	.;D;.;.;.;D;.;.;.;.;P;.;.;.;.;.;.;.
Vest4		0.42
MutPred		0.35		Loss of catalytic residue at L95 (P = 0.0479);Loss of catalytic residue at L95 (P = 0.0479);Loss of catalytic residue at L95 (P = 0.0479);Loss of catalytic residue at L95 (P = 0.0479);.;Loss of catalytic residue at L95 (P = 0.0479);.;Loss of catalytic residue at L95 (P = 0.0479);.;.;Loss of catalytic residue at L95 (P = 0.0479);Loss of catalytic residue at L95 (P = 0.0479);Loss of catalytic residue at L95 (P = 0.0479);.;Loss of catalytic residue at L95 (P = 0.0479);Loss of catalytic residue at L95 (P = 0.0479);.;.;
MVP		0.96
MPC		0.44
ClinPred		0.68	D
GERP RS		3.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.11
gMVP		0.47

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: rs1555596670; hg19: chr17-41256916;