17-43104153-A-T

Position:

• chr17-43104153-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_007294.4(BRCA1):​c.410T>A​(p.Leu137His) 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L137F) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: BRCA1 NM_007294.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.94

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=0.23801515).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA1	NM_007294.4	c.410T>A	p.Leu137His	missense_variant	6/23	ENST00000357654.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA1	ENST00000357654.9	c.410T>A	p.Leu137His	missense_variant	6/23	1	NM_007294.4	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Quest Diagnostics Nichols Institute San Juan Capistrano

Apr 02, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Benign	20
DANN	Benign	0.91
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.082
FATHMM_MKL	Benign	0.37	N
LIST_S2	Benign	0.77	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
M_CAP	Pathogenic	0.33	D
MetaRNN	Benign	0.24	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.17	D
MutationAssessor	Benign	1.6	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	0.33	T
PROVEAN	Benign	-0.83	N;N;N;N;N;N;N;N;N;D;N;.;N;N;N;D
REVEL	Uncertain	0.51
Sift	Benign	0.056	T;D;D;D;D;D;D;T;D;D;D;.;D;D;D;D
Sift4G	Benign	0.38	T;T;T;T;T;T;.;.;T;.;T;.;T;.;T;.
Polyphen		0.0060, 0.0050, 0.22	.;B;.;.;.;B;.;B;.;.;B;.;.;.;.;.
Vest4		0.34
MutPred		0.34		Loss of stability (P = 0.0055);Loss of stability (P = 0.0055);Loss of stability (P = 0.0055);Loss of stability (P = 0.0055);.;Loss of stability (P = 0.0055);.;Loss of stability (P = 0.0055);.;.;Loss of stability (P = 0.0055);Loss of stability (P = 0.0055);Loss of stability (P = 0.0055);.;Loss of stability (P = 0.0055);Loss of stability (P = 0.0055);
MVP		0.84
MPC		0.12
ClinPred		0.44	T
GERP RS		4.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.11
gMVP		0.46

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: rs751078452; hg19: chr17-41256170;