17-61801348-C-G

Variant names:

• chr17-61801348-C-G
• rs149364097
• NM_032043.3:c.1045G>C

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PP3_Moderate PP5_Very_Strong

The NM_032043.3(BRIP1):​c.1045G>C​(p.Ala349Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000341 in 1,613,812 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A349S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000034 (0 hom.)
• Consequence: BRIP1 NM_032043.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:15 O:1
• Conservation: PhyloP100: 2.77
• Publications: 44 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: Pathogenic. The variant received 10 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.878
• PP5: Variant 17-61801348-C-G is Pathogenic according to our data. Variant chr17-61801348-C-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 30535.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRIP1	NM_032043.3	c.1045G>C	p.Ala349Pro	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.1045G>C	p.Ala349Pro	missense_variant	Exon 8 of 20	1	NM_032043.3	ENSP00000259008.2

Frequencies

GnomAD3 genomes AF: 0.0000395 AC: 6 AN: 152040 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000966

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: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000159 AC: 4 AN: 251328 AF XY: 0.00

Gnomad AFR exome AF: 0.000123

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: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000335 AC: 49 AN: 1461772 Hom.: 0 Cov.: 32 AF XY: 0.0000261 AC XY: 19 AN XY: 727188

African (AFR) AF: 0.0000598 AC: 2 AN: 33472

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39686

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.0000396 AC: 44 AN: 1111928

Other (OTH) AF: 0.0000331 AC: 2 AN: 60392

GnomAD4 genome AF: 0.0000395 AC: 6 AN: 152040 Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3 AN XY: 74248

African (AFR) AF: 0.0000966 AC: 4 AN: 41404

American (AMR) AF: 0.00 AC: 0 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10582

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

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68000

Other (OTH) AF: 0.00 AC: 0 AN: 2086

Alfa AF: 0.0000565 Hom.: 0

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000247 AC: 3

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:15 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:4

Feb 03, 2025

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.A349P variant (also known as c.1045G>C), located in coding exon 7 of the BRIP1 gene, results from a G to C substitution at nucleotide position 1045. The alanine at codon 349 is replaced by proline, an amino acid with highly similar properties. This alteration was detected in a stillborn fetus delivered at a gestational age of 22 weeks who had distinctive characteristics of severe Fanconi anemia. Genetic analysis revealed that the fetus carried this alteration as well as the p.R798* nonsense mutation in the BRIP1 gene (Levran O et al. Nat. Genet. 2005; 37:931-3). This alteration has also been identified in patients with ovarian cancer in multiple separate studies (Kanchi KL et al. Nat Commun. 2014; 5:3156; Carter NJ et al. Gynecol. Oncol., 2018 12;151:481-488; Moyer CL et al. Cancer Res. 2020 Feb 2015;80(4):857-867). This alteration was observed within 1 of 64523 individuals with a personal history of breast cancer (Easton DF et al. J Med Genet, 2016 May;53:298-309). This variant was also reported in 4/60,466 breast cancer cases and in 1/53,461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). Functional studies revealed that this alteration has significantly impaired helicase activity leading to decreased cell survival upon exposure to DNA damaging agents (Wu Y et al. Blood. 2010; 116(19):3780-91; Sommers JA et al. J. Biol. Chem. 2014 Jul; 289(29):19928-41). Furthermore, this alteration is able to act in a dominant-negative fashion in BRIP1-sufficient cells (Wu Y et al. Blood. 2010; 116(19):3780-91). The functional impairment of this alteration is likely due to the disruption of a critical iron-sulfur cluster domain which is conserved in other members of this helicase family of proteins (Rudolf J et al. Mol. Cell. 2006 Sep; 23(6):801-8; internal structural analysis). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Dec 13, 2021

Sema4, Sema4

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Mar 11, 2025

Color Diagnostics, LLC DBA Color Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces alanine with proline at codon 349 of the BRIP1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function. Functional studies have reported this variant as a dominant negative mutation, with the mutant protein exhibiting defective helicase activity and impaired response to DNA damaging agent (PMID: 16973432, 20639400, 20980836, 23935105, 24895130, 27107905, 31822495). This variant has also been reported in at least nine individuals affected with ovarian cancer (PMID: 24448499, 30322717, 31265121, 31341520, 31822495, 34585738) and five individuals affected with breast cancer (PMID: 33471991, 34585738). This variant has been reported in compound heterozygosity with a pathogenic truncation variant in an individual affected with Fanconi anemia (PMID: 16116426). This variant has been identified in 5/282726 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. -

Dec 12, 2023

Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Fanconi anemia complementation group J Pathogenic:3

Nov 11, 2010

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

May 07, 2019

Revvity Omics, Revvity

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 07, 2011

Leiden Open Variation Database

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: curation

Curator: Arleen D. Auerbach. Submitter to LOVD: Arleen D. Auerbach. -

Familial cancer of breast Pathogenic:2

Jun 01, 2023

Myriad Genetics, Inc.

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 20639400]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 16116424]. -

Feb 29, 2024

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Jan 17, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 349 of the BRIP1 protein (p.Ala349Pro). This variant is present in population databases (rs149364097, gnomAD 0.008%). This missense change has been observed in individual(s) with breast, ovarian or prostate cancer and/or Fanconia anemia (PMID: 16116424, 24448499, 30322717, 31822495, 34585738, 36446039). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as c.1186G>C. ClinVar contains an entry for this variant (Variation ID: 30535). 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) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on BRIP1 protein function. Experimental studies have shown that this missense change affects BRIP1 function (PMID: 16973432, 20639400, 27107905, 33619228). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

BRIP1-related disorder Pathogenic:1

May 25, 2023

PreventionGenetics, part of Exact Sciences

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The BRIP1 c.1045G>C variant is predicted to result in the amino acid substitution p.Ala349Pro. It has been reported in individuals with ovarian cancer (see for example - Kanchi et al. 2014. PubMed ID: 24448499, Table 2; Carter et al. 2018. PubMed ID: 30322717, Table S1; Zhu et al. 2020. PubMed ID: 31265121, Table S2). It has also been reported in the compound heterozygous state in an individual with Fanconi anemia who had an additional nonsense variant in BRIP1 (c.2533C>T, p.Arg798* in Levran et al. 2005. PubMed ID: 16116424, Table 1). Experimental studies indicate that this variant impacts protein function (Rudolf et al. 2006. PubMed ID: 16973432; Wu et al. 2009. PubMed ID: 19519404; Guo et al. 2016. PubMed ID: 27107905; Sommers et al. 2014. PubMed ID: 24895130; Moyer et al. 2019. PubMed ID: 31822495). It is reported in 0.012% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/17-59878709-C-G) and is interpreted as likely pathogenic and pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/30535/). This variant is interpreted as likely pathogenic. -

not provided Pathogenic:1

Jan 31, 2025

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

A case-control study has found a significant association with breast and ovarian cancer, with the risk being particularly strong for ovarian cancer, and not statistically significant for breast cancer alone (PMID: 36169650); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 26790966, 24728327, 29922827, 21345144, 16973432, 25374583, 27107905, 24895130, 20980836, 26596371, 26921362, 28911102, 30322717, 31822495, 29019354, 35245693, 23935105, 33619228, 32542039, 34585738, 32427313, 24448499, 20639400, 33471991, Milano2023[Pre-Print], 34301788, 38781545, 16116424, 36446039, 36169650, 39096152) -

Familial ovarian cancer Pathogenic:1

Mar 13, 2025

Molecular Pathology, Peter Maccallum Cancer Centre

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary breast ovarian cancer syndrome Pathogenic:1

Jun 27, 2022

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: BRIP1 c.1045G>C (p.Ala349Pro) results in a non-conservative amino acid change located in the Fe-S domain in the helicase core (Moyer_2019) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.3e-05 in 263562 control chromosomes (gnomAD and publications). c.1045G>C has been reported in the literature in multiple individuals affected with breast and/or ovarian cancer (e.g. Kanchi_2014, Carter_2018, Zhu_2019, Moyer_2019, Flaum_2022). In addition, this variant has been reported in a compound heterozygous state with another pathogenic BRIP1 variant (p.R798X) in one individual affected with Fanconi anemia (Levran_2005). These data indicate that the variant is very likely to be associated with disease. A case-control study has reported the variant to be associated with significantly increased risk of breast cancer and epithelial ovarian cancer (OR = 37.7; 95% CI 5.3-444.2, P=0.0001; Flaum_2022). Multiple functional studies report the A349P variant affects protein function based on abolished helicase activity, DNA binding activity, translocase activity and effects of MMC on chromosome fragmentation, cell viability, and cell cycle, but has normal protein stability (Rudolf_2006, Wu_2009, Guo_2016, Sommers_2014, Moyer_2019, Odermatt_2020). Seven assessments for this variant have been submitted to ClinVar after 2014 and all classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Diffuse intrinsic pontine glioma Pathogenic:1

Jan 15, 2016

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

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Other:1

Sep 19, 2013

ITMI

Significance: not provided

Review Status: no classification provided

Collection Method: reference population

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Pathogenic	0.17
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.53	D;.
Eigen	Uncertain	0.19
Eigen_PC	Benign	0.16
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.85	T;T
M_CAP	Uncertain	0.24	D
MetaRNN	Pathogenic	0.88	D;D
MetaSVM	Uncertain	-0.084	T
MutationAssessor	Benign	1.9	L;L
PhyloP100		2.8
PrimateAI	Benign	0.40	T
PROVEAN	Uncertain	-2.9	D;.
REVEL	Uncertain	0.64
Sift	Uncertain	0.020	D;.
Sift4G	Uncertain	0.041	D;T
Polyphen		1.0	D;.
Vest4		0.78
MVP		0.85
MPC		0.66
ClinPred		0.89	D
GERP RS		2.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.76
gMVP		0.76
Mutation Taster		=24/76	disease causing (ClinVar)

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: rs149364097; hg19: chr17-59878709;