chr17-43124019-G-C

Position:

• chr17-43124019-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PM5 PP3

The NM_007294.4(BRCA1):​c.78C>G​(p.Ile26Met) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. 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. I26L) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: BRCA1 NM_007294.4 missense, splice_region
• Scores: Splicing: ADA: 0.0008053
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: 0.560

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 Likely_pathogenic. Variant got 7 ACMG points.

• PM1: In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 4 benign, 17 uncertain in NM_007294.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-43124020-A-T is described in ClinVar as [Pathogenic]. Clinvar id is 252890.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.819

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA1	NM_007294.4	c.78C>G	p.Ile26Met	missense_variant, splice_region_variant	2/23	ENST00000357654.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA1	ENST00000357654.9	c.78C>G	p.Ile26Met	missense_variant, splice_region_variant	2/23	1	NM_007294.4	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

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	Pathogenic	0.84
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.44	.;T;.;.;.;T;.;T;T;.;T;D;.
Eigen	Uncertain	0.23
Eigen_PC	Benign	0.048
FATHMM_MKL	Benign	0.56	D
LIST_S2	Uncertain	0.94	D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.72	D
MetaRNN	Pathogenic	0.82	D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.31	D
MutationAssessor	Uncertain	2.8	M;M;M;M;M;.;.;.;.;.;.;.;.
MutationTaster	Benign	0.66	D;D;D;D;D;D;D;D;N;N;N;N;N;N
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-0.43	N;N;N;N;N;N;N;.;N;N;N;D;D
REVEL	Uncertain	0.62
Sift	Uncertain	0.0010	D;D;D;D;D;D;D;.;D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;.;D;.;D;.;D;.;.
Polyphen		0.99, 1.0, 1.0	.;D;.;.;D;.;D;.;.;.;.;.;.
Vest4		0.71
MutPred		0.73		Loss of catalytic residue at E29 (P = 0.2244);Loss of catalytic residue at E29 (P = 0.2244);Loss of catalytic residue at E29 (P = 0.2244);Loss of catalytic residue at E29 (P = 0.2244);Loss of catalytic residue at E29 (P = 0.2244);Loss of catalytic residue at E29 (P = 0.2244);Loss of catalytic residue at E29 (P = 0.2244);Loss of catalytic residue at E29 (P = 0.2244);Loss of catalytic residue at E29 (P = 0.2244);Loss of catalytic residue at E29 (P = 0.2244);Loss of catalytic residue at E29 (P = 0.2244);Loss of catalytic residue at E29 (P = 0.2244);Loss of catalytic residue at E29 (P = 0.2244);
MVP		0.91
MPC		0.44
ClinPred		0.97	D
GERP RS		-0.66
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.74
gMVP		0.68

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00081
dbscSNV1_RF	Benign	0.048
SpliceAI score (max)		0.070		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: rs1555600862; hg19: chr17-41276036;