chr17-43067622-A-G

Position:

• chr17-43067622-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PM5 PP3_Moderate

The NM_007294.4(BRCA1):​c.5060T>C​(p.Val1687Ala) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,459,638 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. V1687D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: BRCA1 NM_007294.4 missense
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: 5.60

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 8 ACMG points.

• PM1: In a hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 7 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 chr17-43067622-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 433721.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.859

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA1	NM_007294.4	c.5060T>C	p.Val1687Ala	missense_variant	16/23	ENST00000357654.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA1	ENST00000357654.9	c.5060T>C	p.Val1687Ala	missense_variant	16/23	1	NM_007294.4	P4

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459638 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726294

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 30

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	0.79
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.39
CADD	Uncertain	26
DANN	Uncertain	1.0
Eigen	Pathogenic	0.72
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.94	D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.83	D
MetaRNN	Pathogenic	0.86	D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.88	D
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.67	T
PROVEAN	Uncertain	-3.1	D;N;.;D;.;N;D;D;N;D
REVEL	Pathogenic	0.86
Sift	Uncertain	0.0010	D;D;.;D;.;D;D;D;D;D
Sift4G	Uncertain	0.016	D;D;D;D;D;D;D;.;.;D
Polyphen		0.85, 1.0	.;P;.;.;.;.;.;.;D;.
Vest4		0.82
MVP		0.98
MPC		0.15
ClinPred		0.96	D
GERP RS		5.2
Varity_R		0.94
gMVP		0.74

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: rs1555579627; hg19: chr17-41219639;