rs80357103

chr17-43094640-C-Achr17-43094640-C-Gchr17-43094640-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 10P and 8B. PVS1 PM2 BP6_Very_Strong

The ENST00000497488.2(BRCA1):c.3G>T(p.Met1?) variant causes a start lost 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 Benign (★★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: BRCA1 ENST00000497488.2 start_lost
• Clinical Significance: Benign reviewed by expert panel B:1
• Conservation: PhyloP100: 1.53

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 2 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PM2: Very rare variant in population databases, with high coverage
• BP6: Variant 17-43094640-C-A is Benign according to our data. Variant chr17-43094640-C-A is described in ClinVar as [Benign]. Clinvar id is 812549.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA1	NM_007294.4	c.891G>T	p.Met297Ile	missense_variant	10/23	ENST00000357654.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA1	ENST00000357654.9	c.891G>T	p.Met297Ile	missense_variant	10/23	1	NM_007294.4	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1 Benign:1

Benign, reviewed by expert panel

curation

Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)

Jun 18, 2019

IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 1 based on posterior probability = 0.000632 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.42
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.070
Cadd	Benign	20
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.53	D;.;.;.;T;T;.;.;T
Eigen	Uncertain	0.21
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Uncertain	0.88	D;D;D;D;D;D;D;D;D
M_CAP	Benign	0.069	D
MetaRNN	Uncertain	0.45	T;T;T;T;T;T;T;D;T
MetaSVM	Benign	-0.70	T
MutationAssessor	Uncertain	2.4	M;M;.;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;N;N;N;N;N
PrimateAI	Benign	0.45	T
PROVEAN	Uncertain	-3.2	D;D;D;D;.;D;D;D;D
REVEL	Uncertain	0.59
Sift	Uncertain	0.023	D;D;D;D;.;D;D;D;D
Sift4G	Benign	0.061	T;T;T;T;.;T;.;T;D
Polyphen		0.074	B;.;.;B;.;.;.;.;.
Vest4		0.38
MutPred		0.42		Gain of helix (P = 0.0325);Gain of helix (P = 0.0325);.;Gain of helix (P = 0.0325);.;Gain of helix (P = 0.0325);.;.;Gain of helix (P = 0.0325);
MVP		0.90
MPC		0.098
ClinPred		0.86	D
GERP RS		4.0
Varity_R		0.27
gMVP		0.19

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: rs80357103; hg19: chr17-41246657;