17-43049150-T-C

Variant names:

• chr17-43049150-T-C
• rs397509274
• NM_007294.4:c.5377A>G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_007294.4(BRCA1):​c.5377A>G​(p.Lys1793Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as not provided (no stars).

• Frequency: Genomes: not found (cov: 31)
• Consequence: BRCA1 NM_007294.4 missense
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: 2.06

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 4 ACMG points.

• PM1: In a domain BRCT 2 (size 99) in uniprot entity BRCA1_HUMAN there are 69 pathogenic changes around while only 15 benign (82%) in NM_007294.4
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA1	NM_007294.4	c.5377A>G	p.Lys1793Glu	missense_variant	Exon 21 of 23	ENST00000357654.9	NP_009225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9	c.5377A>G	p.Lys1793Glu	missense_variant	Exon 21 of 23	1	NM_007294.4	ENSP00000350283.3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

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	0.14
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.16
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.12	.;T;.;T;T;T;.;.
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.93	D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.39	D
MetaRNN	Uncertain	0.69	D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.76	D
MutationAssessor	Uncertain	2.3	.;M;.;.;.;.;.;.
PrimateAI	Benign	0.44	T
PROVEAN	Uncertain	-2.5	D;N;.;.;.;.;N;N
REVEL	Pathogenic	0.69
Sift	Benign	0.090	T;D;.;.;.;.;D;T
Sift4G	Uncertain	0.0050	D;D;D;D;D;D;D;D
Polyphen		0.49, 0.28	.;P;.;.;.;B;.;.
Vest4		0.49
MVP		0.84
MPC		0.23
ClinPred		0.95	D
GERP RS		5.4
Varity_R		0.69
gMVP		0.67

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: rs397509274; hg19: chr17-41201167;