17-43106467-A-T

Variant names:

• chr17-43106467-A-T
• rs80357033
• NM_007294.4:c.201T>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_007294.4(BRCA1):​c.201T>A​(p.Asp67Glu) 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. 13/21 in silico tools predict 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. D67Y) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: BRCA1 NM_007294.4 missense
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: 0.262

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.18324041).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA1	NM_007294.4	c.201T>A	p.Asp67Glu	missense_variant	Exon 4 of 23	ENST00000357654.9	NP_009225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9	c.201T>A	p.Asp67Glu	missense_variant	Exon 4 of 23	1	NM_007294.4	ENSP00000350283.3

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

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Brotman Baty Institute, University of Washington

Significance: not provided

Review Status: no classification provided

Collection Method: in vitro

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.030
CADD	Benign	11
DANN	Benign	0.61
DEOGEN2	Benign	0.095	.;T;.;.;.;.;T;.;.;T;T;T;T;.
Eigen	Benign	-0.60
Eigen_PC	Benign	-0.49
FATHMM_MKL	Benign	0.33	N
LIST_S2	Benign	0.69	T;T;T;T;T;T;T;T;T;T;T;T;T;T
M_CAP	Benign	0.083	D
MetaRNN	Benign	0.18	T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.28	T
MutationAssessor	Benign	1.3	L;L;L;L;.;L;.;.;.;.;.;.;.;.
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.37	N;N;N;N;N;N;N;N;N;.;N;N;N;.
REVEL	Uncertain	0.56
Sift	Benign	1.0	T;T;T;T;T;T;T;T;T;.;T;T;T;.
Sift4G	Benign	0.73	T;T;T;T;T;T;.;T;T;.;T;T;.;.
Polyphen		0.65, 0.24, 0.0	.;P;.;.;.;B;.;.;B;.;.;.;.;.
Vest4		0.60
MutPred		0.73		Gain of disorder (P = 0.1038);Gain of disorder (P = 0.1038);Gain of disorder (P = 0.1038);Gain of disorder (P = 0.1038);.;Gain of disorder (P = 0.1038);Gain of disorder (P = 0.1038);.;Gain of disorder (P = 0.1038);Gain of disorder (P = 0.1038);Gain of disorder (P = 0.1038);Gain of disorder (P = 0.1038);Gain of disorder (P = 0.1038);.;
MVP		0.83
MPC		0.082
ClinPred		0.033	T
GERP RS		1.1
Varity_R		0.079
gMVP		0.21

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: rs80357033; hg19: chr17-41258484;