NM_032043.3:c.995G>A

Variant names:

• chr17-61801398-C-T
• rs876660521
• NM_032043.3:c.995G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_032043.3(BRIP1):​c.995G>A​(p.Cys332Tyr) 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. 17/22 in silico tools predict 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. C332R) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: BRIP1 NM_032043.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:5
• Conservation: PhyloP100: -1.01
• Publications: 4 publications found

Genes affected

BRIP1 (HGNC:20473): (BRCA1 interacting helicase 1) The protein encoded by this gene is a member of the RecQ DEAH helicase family and interacts with the BRCT repeats of breast cancer, type 1 (BRCA1). The bound complex is important in the normal double-strand break repair function of breast cancer, type 1 (BRCA1). This gene may be a target of germline cancer-inducing mutations. [provided by RefSeq, Jul 2008]

BRIP1 Gene-Disease associations (from GenCC):

• familial ovarian cancer

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• Fanconi anemia

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, Illumina
• Fanconi anemia complementation group J

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• hereditary breast carcinoma

  Inheritance: AD Classification: STRONG, LIMITED, NO_KNOWN Submitted by: ClinGen, Genomics England PanelApp, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• colorectal adenoma

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13227344).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRIP1	NM_032043.3	c.995G>A	p.Cys332Tyr	missense_variant	Exon 8 of 20	ENST00000259008.7	NP_114432.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRIP1	ENST00000259008.7	c.995G>A	p.Cys332Tyr	missense_variant	Exon 8 of 20	1	NM_032043.3	ENSP00000259008.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251268 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Jul 31, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The BRIP1 c.995G>A (p.Cys332Tyr) variant has not been reported in individuals with BRIP1-related conditions in the published literature. The frequency of this variant in the general population, 0.000004 (1/251268 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant. -

Oct 09, 2015

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is denoted BRIP1 c.995G>A at the cDNA level, p.Cys332Tyr (C332Y) at the protein level, and results in the change of a Cysteine to a Tyrosine (TGC>TAC). This variant has not, to our knowledge, been published in the literature as being pathogenic or benign. BRIP1 Cys332Tyr was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Cysteine and Tyrosine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRIP1 Cys332Tyr occurs at a position that is not conserved and is located in the Fe-S and helicase ATP-binding domains (Cantor 2011, UniProt). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available evidence, it is unclear whether BRIP1 Cys332Tyr is pathogenic or benign. We consider it to be a variant of uncertain significance. -

Hereditary cancer-predisposing syndrome Uncertain:2

Sep 12, 2022

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces cysteine with tyrosine at codon 332 of the BRIP1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 1/251268 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. -

Feb 07, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.C332Y variant (also known as c.995G>A), located in coding exon 7 of the BRIP1 gene, results from a G to A substitution at nucleotide position 995. The cysteine at codon 332 is replaced by tyrosine, an amino acid with highly dissimilar properties. This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Familial cancer of breast;C1836860:Fanconi anemia complementation group J Uncertain:1

Mar 06, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 332 of the BRIP1 protein (p.Cys332Tyr). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with BRIP1-related conditions. ClinVar contains an entry for this variant (Variation ID: 233613). 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 BRIP1 protein function with a negative predictive value of 80%. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	0.74
DANN	Benign	0.20
DEOGEN2	Benign	0.18	T;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.027	N
LIST_S2	Benign	0.51	T;T
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.13	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.81	L;L
PhyloP100		-1.0
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.56	N;.
REVEL	Benign	0.086
Sift	Benign	1.0	T;.
Sift4G	Benign	0.98	T;T
Polyphen		0.0010	B;.
Vest4		0.27
MutPred		0.56		Loss of methylation at K333 (P = 0.0177);Loss of methylation at K333 (P = 0.0177);
MVP		0.38
MPC		0.28
ClinPred		0.014	T
GERP RS		-4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.035
gMVP		0.54

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

Other links and lift over

dbSNP: rs876660521; hg19: chr17-59878759;