17-43095861-C-T

Position:

• chr17-43095861-C-T

Variant summary

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

The NM_007294.4(BRCA1):​c.655G>A​(p.Asp219Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,448 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: BRCA1 NM_007294.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:1
• Conservation: PhyloP100: 0.185

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]

BRCA1 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA1	NM_007294.4	c.655G>A	p.Asp219Asn	missense_variant	9/23	ENST00000357654.9	NP_009225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9	c.655G>A	p.Asp219Asn	missense_variant	9/23	1	NM_007294.4	ENSP00000350283.3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.00000797 AC: 2 AN: 250952 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135632

Gnomad AFR exome AF: 0.0000617

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461448 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727030

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Jan 13, 2016	- -
Uncertain significance, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA1)	Dec 17, 2010	- -

Hereditary cancer-predisposing syndrome Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Feb 21, 2023	This missense variant replaces aspartic acid with asparagine at codon 219 of the BRCA1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). A functional study has reported that this variant does not impact BRCA1 function in a E3 ubiquitin ligase assay (PMID: 25823446). This variant has been reported in one individual each affected with breast cancer and colorectal cancer (PMID: 25980754; doi: 10.29289/2594539420210032). This variant has been identified in 2/250952 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 07, 2016	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jul 18, 2016

This variant is denoted BRCA1 c.655G>A at the cDNA level, p.Asp219Asn (D219N) at the protein level, and results in the change of an Aspartic Acid to an Asparagine (GAT>AAT). Using alternate nomenclature, this variant would be defined as BRCA1 774G>A. This variant has been reported in an individual with a Lynch syndrome-associated tumor and/or colon polyps (Yurgelun 2015). BRCA1 Asp219Asn was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Aspartic Acid and Asparagine differ in some properties, this is considered a semi-conservative amino acid substitution. BRCA1 Asp219Asn occurs at a position that is not conserved and is located in a region known to interact with BRD7 and MB2 (Wang 1998, Harte 2010). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available evidence, it is unclear whether BRCA1 Asp219Asn is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. -

Familial cancer of breast Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

MGZ Medical Genetics Center

Feb 09, 2024

ACMG codes applied following ENIGMA VCEP rules: PM2_SUP, PP3 -

Hereditary breast ovarian cancer syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 07, 2023

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. Experimental studies have shown that this missense change does not substantially affect BRCA1 function (PMID: 25823446). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt BRCA1 protein function. ClinVar contains an entry for this variant (Variation ID: 55655). This variant has not been reported in the literature in individuals affected with BRCA1-related conditions. This variant is present in population databases (rs273902779, gnomAD 0.007%). This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 219 of the BRCA1 protein (p.Asp219Asn). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Benign	-0.025	T
BayesDel_noAF	Benign	-0.090
CADD	Benign	13
DANN	Uncertain	0.99
DEOGEN2	Benign	0.078	.;T;.;.;.;.;T;.;.;T;.;T;T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.015	N
LIST_S2	Benign	0.85	D;T;T;T;T;T;T;T;T;T;T;T;T
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.031	T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.30	T
MutationAssessor	Benign	0.075	N;N;N;N;.;N;.;.;.;.;.;.;.
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-1.8	N;N;N;N;N;N;N;N;N;N;N;N;N
REVEL	Uncertain	0.39
Sift	Benign	0.27	T;T;T;T;T;T;T;T;T;T;T;T;T
Sift4G	Benign	0.29	T;T;T;T;T;T;.;T;T;T;.;T;.
Polyphen		0.0010, 0.0020	.;B;.;.;.;B;.;.;B;.;.;.;.
Vest4		0.13
MutPred		0.19		Loss of phosphorylation at S217 (P = 0.1333);Loss of phosphorylation at S217 (P = 0.1333);Loss of phosphorylation at S217 (P = 0.1333);Loss of phosphorylation at S217 (P = 0.1333);.;Loss of phosphorylation at S217 (P = 0.1333);.;.;Loss of phosphorylation at S217 (P = 0.1333);Loss of phosphorylation at S217 (P = 0.1333);.;Loss of phosphorylation at S217 (P = 0.1333);.;
MVP		0.57
MPC		0.079
ClinPred		0.026	T
GERP RS		-1.4
Varity_R		0.031
gMVP		0.15

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.34		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.34		Position offset: -15

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs273902779; hg19: chr17-41247878;