rs777515082

Positions:

• chr17-43099811-T-C
• chr17-43099811-T-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Moderate BP6_Moderate

The NM_007294.4(BRCA1):​c.511A>G​(p.Ile171Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,278 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: BRCA1 NM_007294.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.484

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_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.116542995).
• BP6: Variant 17-43099811-T-C is Benign according to our data. Variant chr17-43099811-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 431182.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA1	NM_007294.4	c.511A>G	p.Ile171Val	missense_variant	7/23	ENST00000357654.9	NP_009225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9	c.511A>G	p.Ile171Val	missense_variant	7/23	1	NM_007294.4	ENSP00000350283	P4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461278 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727028

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.: 31

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Cancer Genetics and Genomics Laboratory, British Columbia Cancer Agency

Apr 18, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.096
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
CADD	Benign	0.23
DANN	Benign	0.29
DEOGEN2	Benign	0.083	.;T;.;.;.;.;.;T;.;T;.;T;T;.;T;T
Eigen	Benign	-0.79
Eigen_PC	Benign	-0.82
FATHMM_MKL	Benign	0.021	N
LIST_S2	Benign	0.82	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.12	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.014	T
MutationAssessor	Benign	1.1	L;L;L;L;.;L;.;.;.;.;.;.;.;.;.;.
MutationTaster	Benign	1.0	N;N;N;N;N;N;N;N;N;N;N;N;N;N
PrimateAI	Benign	0.31	T
PROVEAN	Benign	0.12	N;N;N;N;N;N;N;N;N;N;N;.;N;N;N;N
REVEL	Uncertain	0.55
Sift	Benign	0.79	T;T;T;T;T;T;T;T;T;T;T;.;T;T;T;T
Sift4G	Benign	0.76	T;T;T;T;T;T;.;.;T;.;T;.;T;.;T;.
Polyphen		0.070, 0.050, 0.013, 0.0	.;B;.;.;.;B;.;B;.;.;B;.;.;.;.;.
Vest4		0.27
MutPred		0.24		Loss of catalytic residue at P173 (P = 0.0559);Loss of catalytic residue at P173 (P = 0.0559);Loss of catalytic residue at P173 (P = 0.0559);Loss of catalytic residue at P173 (P = 0.0559);.;Loss of catalytic residue at P173 (P = 0.0559);.;.;.;.;Loss of catalytic residue at P173 (P = 0.0559);Loss of catalytic residue at P173 (P = 0.0559);Loss of catalytic residue at P173 (P = 0.0559);.;Loss of catalytic residue at P173 (P = 0.0559);.;
MVP		0.59
MPC		0.070
ClinPred		0.017	T
GERP RS		0.38
Varity_R		0.021
gMVP		0.18

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs777515082; hg19: chr17-41251828;