rs1402064476

chr17-43124048-C-Achr17-43124048-C-Gchr17-43124048-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1 PM2 BP4

The NM_007294.4(BRCA1):c.49G>T(p.Ala17Ser) 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. A17D) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: BRCA1 NM_007294.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2 O:1
• Conservation: PhyloP100: 3.52

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 3 ACMG points.

• PM1: In a hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 4 benign, 17 uncertain in NM_007294.4
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.368523).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA1	NM_007294.4	c.49G>T	p.Ala17Ser	missense_variant	2/23	ENST00000357654.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA1	ENST00000357654.9	c.49G>T	p.Ala17Ser	missense_variant	2/23	1	NM_007294.4	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Mar 21, 2019

- -

Hereditary breast ovarian cancer syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Breast Center, Key Laboratory of Carcinogenesis and Translational Research

May 01, 2020

- -

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

not provided, no classification provided

in vitro

Brotman Baty Institute, University of Washington

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.0
Cadd	Uncertain	24
Dann	Uncertain	1.0
Eigen	Uncertain	0.26
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Uncertain	0.96	D;D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.42	D
MetaRNN	Benign	0.37	T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.10	D
MutationAssessor	Benign	-0.070	N;N;N;N;N;.;.;.;.;.;.;.;.;.
MutationTaster	Benign	0.91	D;D;D;D;D;D;D;D;D;D;N;N;N;N
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-0.47	N;N;N;N;N;N;N;.;N;N;N;N;N;.
REVEL	Uncertain	0.58
Sift	Benign	0.15	T;D;D;T;T;T;D;.;D;D;D;T;T;.
Sift4G	Benign	0.12	T;D;D;T;T;.;D;.;D;.;D;.;.;.
Polyphen		0.98, 0.90, 0.84	.;D;.;.;P;.;P;.;.;.;.;.;.;.
Vest4		0.48
MutPred		0.27		Gain of methylation at K20 (P = 0.1116);Gain of methylation at K20 (P = 0.1116);Gain of methylation at K20 (P = 0.1116);Gain of methylation at K20 (P = 0.1116);Gain of methylation at K20 (P = 0.1116);Gain of methylation at K20 (P = 0.1116);Gain of methylation at K20 (P = 0.1116);Gain of methylation at K20 (P = 0.1116);Gain of methylation at K20 (P = 0.1116);Gain of methylation at K20 (P = 0.1116);Gain of methylation at K20 (P = 0.1116);Gain of methylation at K20 (P = 0.1116);Gain of methylation at K20 (P = 0.1116);Gain of methylation at K20 (P = 0.1116);
MVP		0.91
MPC		0.11
ClinPred		0.92	D
GERP RS		3.8
Varity_R		0.37
gMVP		0.41

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs1402064476; hg19: chr17-41276065;