17-43106489-T-G

Position:

• chr17-43106489-T-G

Variant summary

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

The NM_007294.4(BRCA1):​c.179A>C​(p.Gln60Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00000125 in 1,604,960 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as not provided (no stars).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: BRCA1 NM_007294.4 missense
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: 4.35

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 zinc_finger_region RING-type (size 41) in uniprot entity BRCA1_HUMAN there are 65 pathogenic changes around while only 6 benign (92%) in NM_007294.4
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA1	NM_007294.4	c.179A>C	p.Gln60Pro	missense_variant	4/23	ENST00000357654.9	NP_009225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9	c.179A>C	p.Gln60Pro	missense_variant	4/23	1	NM_007294.4	ENSP00000350283	P4

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152214 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250812 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135606

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 6.88e-7 AC: 1 AN: 1452746 Hom.: 0 Cov.: 28 AF XY: 0.00000138 AC XY: 1 AN XY: 723084

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000167

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152214 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74366

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000434 Hom.: 0

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	Uncertain	0.46
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.33
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.28	.;T;.;.;.;.;T;.;.;T;T;T;T;.
Eigen	Uncertain	0.32
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.83	T;T;T;T;D;T;T;D;T;T;T;T;D;D
M_CAP	Pathogenic	0.63	D
MetaRNN	Uncertain	0.69	D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.64	D
MutationAssessor	Benign	0.56	N;N;N;N;.;N;.;.;.;.;.;.;.;.
MutationTaster	Benign	0.95	D;D;D;D;D;D;D;D;D;N;N;N;N;N
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-0.20	N;N;N;N;N;N;N;N;N;.;N;N;D;.
REVEL	Pathogenic	0.69
Sift	Benign	0.21	T;D;D;T;D;T;T;T;D;.;D;D;T;.
Sift4G	Uncertain	0.052	T;D;D;D;D;D;.;D;D;.;D;D;.;.
Polyphen		0.068, 0.99, 0.99	.;B;.;.;.;D;.;.;D;.;.;.;.;.
Vest4		0.74
MutPred		0.54		Gain of glycosylation at Q60 (P = 0.0192);Gain of glycosylation at Q60 (P = 0.0192);Gain of glycosylation at Q60 (P = 0.0192);Gain of glycosylation at Q60 (P = 0.0192);.;Gain of glycosylation at Q60 (P = 0.0192);Gain of glycosylation at Q60 (P = 0.0192);.;Gain of glycosylation at Q60 (P = 0.0192);Gain of glycosylation at Q60 (P = 0.0192);Gain of glycosylation at Q60 (P = 0.0192);Gain of glycosylation at Q60 (P = 0.0192);Gain of glycosylation at Q60 (P = 0.0192);.;
MVP		0.89
MPC		0.44
ClinPred		0.44	T
GERP RS		5.2
Varity_R		0.76
gMVP		0.76

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs373655067; hg19: chr17-41258506;