rs960381964

chr17-43094240-A-Cchr17-43094240-A-Gchr17-43094240-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4 BP6

The NM_007294.4(BRCA1):c.1291T>G(p.Leu431Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L431I) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: BRCA1 NM_007294.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -0.0180

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.32188064).
• BP6: Variant 17-43094240-A-C is Benign according to our data. Variant chr17-43094240-A-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1303574.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA1	NM_007294.4	c.1291T>G	p.Leu431Val	missense_variant	10/23	ENST00000357654.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA1	ENST00000357654.9	c.1291T>G	p.Leu431Val	missense_variant	10/23	1	NM_007294.4	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Sep 10, 2019

Not observed in large population cohorts (Lek et al., 2016); Has not been previously published as pathogenic or benign to our knowledge; In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Also known as BRCA1 1410T>G -

Hereditary cancer-predisposing syndrome Benign:1

Likely benign, criteria provided, single submitter

curation

University of Washington Department of Laboratory Medicine, University of Washington

Mar 23, 2023

Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.030
Cadd	Benign	18
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.49	T;.;.;.;T;T;.;.;T
Eigen	Benign	0.10
Eigen_PC	Benign	-0.090
FATHMM_MKL	Benign	0.11	N
LIST_S2	Uncertain	0.87	D;D;D;D;D;D;D;D;D
M_CAP	Uncertain	0.16	D
MetaRNN	Benign	0.32	T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.30	D
MutationAssessor	Uncertain	2.9	M;M;.;.;.;.;.;.;.
MutationTaster	Benign	1.0	N;N;N;N;N;N;N;N;N;N;N;N;N;N
PrimateAI	Benign	0.22	T
PROVEAN	Uncertain	-2.6	D;D;D;D;.;D;D;D;N
REVEL	Uncertain	0.57
Sift	Uncertain	0.012	D;D;D;D;.;D;D;D;D
Sift4G	Benign	0.081	T;T;T;T;.;T;.;T;T
Polyphen		0.99	D;.;.;D;.;.;.;.;.
Vest4		0.38
MutPred		0.46		Loss of sheet (P = 0.0104);Loss of sheet (P = 0.0104);.;Loss of sheet (P = 0.0104);.;Loss of sheet (P = 0.0104);.;.;Loss of sheet (P = 0.0104);
MVP		0.97
MPC		0.33
ClinPred		0.79	D
GERP RS		3.2
Varity_R		0.18
gMVP		0.084

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-41246257;