NM_032043.3(BRIP1):c.2564G>A (p.Arg855His) AND Hereditary cancer-predisposing syndrome

Germline classification:: Uncertain significance (3 submissions)
Last evaluated:: Mar 29, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000116144.18

Allele description [Variation Report for NM_032043.3(BRIP1):c.2564G>A (p.Arg855His)]

NM_032043.3(BRIP1):c.2564G>A (p.Arg855His)

Gene:

BRIP1:BRCA1 interacting helicase 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

17q23.2

Genomic location:

Preferred name:

NM_032043.3(BRIP1):c.2564G>A (p.Arg855His)

Other names:

p.R855H:CGC>CAC

HGVS:

NC_000017.11:g.61693441C>T
NG_007409.2:g.175119G>A
NM_032043.3:c.2564G>AMANE SELECT
NP_114432.2:p.Arg855His
NP_114432.2:p.Arg855His
LRG_300t1:c.2564G>A
LRG_300:g.175119G>A
LRG_300p1:p.Arg855His
NC_000017.10:g.59770802C>T
NM_032043.2:c.2564G>A
p.R855H

Protein change:

R855H

Links:

dbSNP: rs200894063

NCBI 1000 Genomes Browser:

rs200894063

Molecular consequence:

NM_032043.3:c.2564G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Hereditary cancer-predisposing syndrome
Synonyms:: Neoplastic Syndromes, Hereditary; Tumor predisposition; Cancer predisposition; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0015356; MeSH: D009386; MedGen: C0027672

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000214409	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Uncertain significance (Mar 29, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 26315354, 26921362, 31206626 Citation Link,
SCV000689345	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Jun 21, 2022)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 25980754, 26921362, 25741868
SCV002533632	Sema4, Sema4	criteria provided, single submitter (Sema4 Curation Guidelines)	Uncertain significance (Dec 16, 2021)	germline	curation	PubMed (5) [See all records that cite these PMIDs] 25980754, 26921362, 31822495, 26315354, 33471991 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000214409

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Uncertain significance
(Mar 29, 2023)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

Citation Link,

SCV000689345

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Jun 21, 2022)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

SCV002533632

Sema4, Sema4

criteria provided, single submitter

(Sema4 Curation Guidelines)

Uncertain significance
(Dec 16, 2021)

germline

curation

PubMed (5)
[See all records that cite these PMIDs]

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing, curation

Citations

PubMed

Pathogenic and likely pathogenic variants in PALB2, CHEK2, and other known breast cancer susceptibility genes among 1054 BRCA-negative Hispanics with breast cancer.

Weitzel JN, Neuhausen SL, Adamson A, Tao S, Ricker C, Maoz A, Rosenblatt M, Nehoray B, Sand S, Steele L, Unzeitig G, Feldman N, Blanco AM, Hu D, Huntsman S, Castillo D, Haiman C, Slavin T, Ziv E.

Cancer. 2019 Aug 15;125(16):2829-2836. doi: 10.1002/cncr.32083. Epub 2019 Jun 17.

PubMed [citation]

PMID:: 31206626
PMCID:: PMC7376605

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

See all PubMed Citations (7)

Details of each submission

From Ambry Genetics, SCV000214409.8

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

The p.R855H variant (also known as c.2564G>A), located in coding exon 17 of the BRIP1 gene, results from a G to A substitution at nucleotide position 2564. The arginine at codon 855 is replaced by histidine, an amino acid with highly similar properties. In one study, this alteration was observed in 1/3236 cases with invasive epithelial ovarian cancer and 0/3431 controls (Ramus SJ et al. J. Natl. Cancer Inst. 2015 Nov;107). This variant was also reported in one individual with early onset breast cancer but was absent from controls (Easton DF et al. J. Med. Genet. 2016 05;53:298-309). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Color Diagnostics, LLC DBA Color Health, SCV000689345.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

This missense variant replaces arginine with histidine at codon 855 of the BRIP1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with breast cancer and Lynch syndrome-associated cancer and/or polyps (PMID: 25980754, 26921362). This variant has been identified in 20/282682 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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Sema4, Sema4, SCV002533632.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	PubMed (5)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Jun 2, 2024

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