17-61685878-T-G

Variant names:

• chr17-61685878-T-G
• rs587782244
• NM_032043.3:c.2863A>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_032043.3(BRIP1):​c.2863A>C​(p.Asn955His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000335 in 1,613,462 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N955D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000032 (0 hom.)
• Consequence: BRIP1 NM_032043.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:9 B:1
• Conservation: PhyloP100: 0.719
• Publications: 1 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: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.13261291).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRIP1	NM_032043.3	c.2863A>C	p.Asn955His	missense_variant	Exon 19 of 20	ENST00000259008.7	NP_114432.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRIP1	ENST00000259008.7	c.2863A>C	p.Asn955His	missense_variant	Exon 19 of 20	1	NM_032043.3	ENSP00000259008.2

Frequencies

GnomAD3 genomes AF: 0.0000460 AC: 7 AN: 152166 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000120 AC: 3 AN: 250742 AF XY: 0.00000738

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: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000322 AC: 47 AN: 1461296 Hom.: 0 Cov.: 31 AF XY: 0.0000358 AC XY: 26 AN XY: 726934

African (AFR) AF: 0.00 AC: 0 AN: 33438

American (AMR) AF: 0.00 AC: 0 AN: 44644

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26116

East Asian (EAS) AF: 0.00 AC: 0 AN: 39676

South Asian (SAS) AF: 0.00 AC: 0 AN: 86168

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53370

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 0.0000414 AC: 46 AN: 1111760

Other (OTH) AF: 0.0000166 AC: 1 AN: 60366

GnomAD4 genome AF: 0.0000460 AC: 7 AN: 152166 Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4 AN XY: 74334

African (AFR) AF: 0.0000241 AC: 1 AN: 41452

American (AMR) AF: 0.00 AC: 0 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000882 AC: 6 AN: 68020

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.0000579 Hom.: 0

Bravo AF: 0.0000340

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:9 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3

Feb 05, 2025

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; Observed in individuals with breast or prostate cancer (PMID: 21409391, 25186627, 26921362, 33471991, 35467778); This variant is associated with the following publications: (PMID: 21409391, 26921362, 25186627, 11301010, 33471991, 35467778) -

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The BRIP1 p.Asn955His variant was identified in 1 of 140 proband chromosomes (frequency: 0.007) from individuals or families with breast cancer (Wong 2011). The variant was also identified in dbSNP (ID: rs587782244) as “With Uncertain significance allele”, ClinVar (classified as uncertain significance by Invitae, Ambry Genetics, Gene Dx, and Color). The variant was identified in control databases in 4 of 276552 chromosomes at a frequency of 0.00001 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the European (Non-Finnish) population in 4 of 126408 chromosomes (freq: 0.00003), while it was not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian, European (Finnish), or South Asian populations. The p.Asn955 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

Mar 12, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The BRIP1 c.2863A>C (p.Asn955His) variant in the BRIP1 gene. In the published literature, this variant has been reported in individuals with breast cancer (PMID: 21409391 (2011), 25186627 (2015), 26921362 (2016), 33471991 (2021), see also LOVD (https://databases.lovd.nl/shared/variants/BRIP1)). The frequency of this variant in the general population, 0.000031 (4/128866 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. -

Familial cancer of breast;C1836860:Fanconi anemia complementation group J Uncertain:2

May 20, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 15, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces asparagine, which is neutral and polar, with histidine, which is basic and polar, at codon 955 of the BRIP1 protein (p.Asn955His). This variant is present in population databases (rs587782244, gnomAD 0.003%). This missense change has been observed in individual(s) with breast cancer or prostate cancer (PMID: 21409391, 25186627, 35467778). ClinVar contains an entry for this variant (Variation ID: 142113). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt BRIP1 protein function with a negative predictive value of 95%. 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. -

Hereditary cancer-predisposing syndrome Uncertain:1 Benign:1

Jul 01, 2024

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces asparagine with histidine at codon 955 of the BRIP1 protein. Computational prediction suggests that this variant may not impact protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with breast cancer (PMID 21409391, 25186627, 26921362, 33471991) but not unaffected controls (PMID: 26921362, 33471991). This variant has been identified in 4/282132 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. -

Sep 04, 2024

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 specified Uncertain:1

Oct 02, 2023

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: BRIP1 c.2863A>C (p.Asn955His) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 250742 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2863A>C has been reported in the literature in individuals affected with breast an/or ovarian cancer, and prostate cancer, all without evidence of causality (e.g. Wong_2011, Tung_2015, Easton_2016, Brady_2022). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 21409391, 25186627, 26921362, 35467778). Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

BRIP1-related disorder Uncertain:1

Nov 21, 2023

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The BRIP1 c.2863A>C variant is predicted to result in the amino acid substitution p.Asn955His. This variant has been reported in patients with a personal and/or family history of breast or ovarian cancer (Wong et al. 2011. PubMed ID: 21409391; Tung et al. 2015. PubMed ID: 25186627; Easton. 2016. PubMed ID: 26921362). It has also been reported in an individual with prostate cancer (Table S5, Brady et al. 2022. PubMed ID: 35467778). This variant is reported in 0.0031% of alleles in individuals of European (Non-Finnish) descent in gnomAD. In ClinVar, this variant is interpreted as uncertain by multiple laboratories (https://www.ncbi.nlm.nih.gov/clinvar/variation/142113/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Fanconi anemia complementation group J Uncertain:1

Feb 17, 2022

St. Jude Molecular Pathology, St. Jude Children's Research Hospital

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The BRIP1 c.2863A>C (p.Asn955His) missense change has a maximum frequency of 0.0031% in gnomAD v2.1.1 ( https://gnomad.broadinstitute.org/variant/17-59763239-T-G?dataset=gnomad_r2_1 ). Six of six in silico tools predict a benign effect of this variant on protein function (BP4), but to our knowledge these predictions have not been confirmed by functional assays. This variant has been reported in individuals with hereditary breast and ovarian cancer (PMID: 21409391, 25186627, 26921362). In addition, one individual with this variant is reported in a database of women older than 70 years of age who have never had cancer (FLOSSIES database, https://whi.color.com/variant/17-59763239-T-G). To our knowledge, this variant has not been reported in individuals with Fanconi anemia. In summary, this variant meets criteria to be classified as of uncertain significance based on the ACMG/AMP criteria: BP4. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	12
DANN	Uncertain	0.98
DEOGEN2	Benign	0.13	T;.
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.063	N
LIST_S2	Benign	0.37	T;T
M_CAP	Benign	0.035	D
MetaRNN	Benign	0.13	T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	1.8	L;L
PhyloP100		0.72
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-1.1	N;.
REVEL	Benign	0.080
Sift	Benign	0.089	T;.
Sift4G	Benign	0.40	T;T
Polyphen		0.0010	B;.
Vest4		0.19
MVP		0.70
MPC		0.17
ClinPred		0.036	T
GERP RS		3.0
Varity_R		0.045
gMVP		0.16
Mutation Taster		=95/5	polymorphism

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: rs587782244; hg19: chr17-59763239;