rs1800062

Positions:

• chr17-43115746-C-A
• chr17-43115746-C-G
• chr17-43115746-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1 PM2 BP6

The NM_007294.4(BRCA1):​c.114G>T​(p.Lys38Asn) variant causes a missense 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 Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. K38K) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: BRCA1 NM_007294.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2 O:1
• Conservation: PhyloP100: -0.475

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 zinc_finger_region RING-type (size 41) in uniprot entity BRCA1_HUMAN there are 65 pathogenic changes around while only 6 benign (92%) in NM_007294.4
• PM2: Very rare variant in population databases, with high coverage
• BP6: Variant 17-43115746-C-A is Benign according to our data. Variant chr17-43115746-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 54147.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, not_provided=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA1	NM_007294.4	c.114G>T	p.Lys38Asn	missense_variant	3/23	ENST00000357654.9	NP_009225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9	c.114G>T	p.Lys38Asn	missense_variant	3/23	1	NM_007294.4	ENSP00000350283	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

not provided, no classification provided	in vitro	Brotman Baty Institute, University of Washington	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA1)	Oct 29, 2001	- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jun 17, 2016

Variant summary: The BRCA1 c.114G>T (p.Lys38Asn) variant involves the alteration of a conserved Lys residue located in the central RING motif of BRCA. 3/3 in silico tools predict a damaging outcome for this variant. This variant is absent in 113602 control chromosomes and to our knowledge, it was not reported in HBOC patients via publications either. Functional studies demonstrated the variant not to have an impact on BARD1 and UbcH5a binding and to retain E3 ligase and HDR activity of BRCA1 indicating neutrality. Additionally, the variant was reported in the BIC database to co-occur with a pathogenic BRCA2 variant in one individual further suggesting it to be in the benign spectrum. Considering all evidence, the variant was classified as a VUS-possibly benign until more information becomes available. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.83
BayesDel_addAF	Uncertain	0.063	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.28	.;T;.;.;.;T;.;T;T;.;T;T;.
Eigen	Benign	-0.72
Eigen_PC	Benign	-0.81
FATHMM_MKL	Benign	0.19	N
LIST_S2	Benign	0.80	T;D;D;T;T;D;D;T;T;D;D;D;D
M_CAP	Pathogenic	0.68	D
MetaRNN	Uncertain	0.62	D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.011	D
MutationAssessor	Benign	0.0	N;N;N;N;N;.;.;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;N;N;N;N;N;N;N;N
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	0.0	N;N;N;N;N;N;N;.;N;N;N;D;D
REVEL	Uncertain	0.50
Sift	Benign	0.054	T;D;D;D;D;D;D;.;D;D;D;T;T
Sift4G	Uncertain	0.031	D;D;D;D;D;.;D;.;D;.;D;.;.
Polyphen		0.99, 0.38, 0.80	.;D;.;.;B;.;P;.;.;.;.;.;.
Vest4		0.57
MutPred		0.58		Loss of methylation at K38 (P = 2e-04);Loss of methylation at K38 (P = 2e-04);Loss of methylation at K38 (P = 2e-04);Loss of methylation at K38 (P = 2e-04);Loss of methylation at K38 (P = 2e-04);Loss of methylation at K38 (P = 2e-04);Loss of methylation at K38 (P = 2e-04);Loss of methylation at K38 (P = 2e-04);Loss of methylation at K38 (P = 2e-04);Loss of methylation at K38 (P = 2e-04);Loss of methylation at K38 (P = 2e-04);Loss of methylation at K38 (P = 2e-04);Loss of methylation at K38 (P = 2e-04);
MVP		0.53
MPC		0.42
ClinPred		0.82	D
GERP RS		-10
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.59
gMVP		0.57

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: rs1800062; hg19: chr17-41267763; COSMIC: COSV58795759;