rs80357325

Variant names:

• chr17-43099814-G-A
• rs80357325
• NM_007294.4:c.508C>T

Your query was ambiguous. Multiple possible variants found:

• chr17-43099814-G-A
• chr17-43099814-G-C
• chr17-43099814-G-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Moderate BP6_Very_Strong

The NM_007294.4(BRCA1):​c.508C>T​(p.Arg170Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000123 in 1,461,236 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 Benign (★★★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: BRCA1 NM_007294.4 missense
• Clinical Significance: Benign reviewed by expert panel U:7 B:5
• Conservation: PhyloP100: 0.685

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]

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.08125824).
• BP6: Variant 17-43099814-G-A is Benign according to our data. Variant chr17-43099814-G-A is described in ClinVar as [Benign]. Clinvar id is 55393.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43099814-G-A is described in Lovd as [Benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA1	NM_007294.4	c.508C>T	p.Arg170Trp	missense_variant	Exon 7 of 23	ENST00000357654.9	NP_009225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9	c.508C>T	p.Arg170Trp	missense_variant	Exon 7 of 23	1	NM_007294.4	ENSP00000350283.3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.0000119 AC: 3 AN: 251458 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135900

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000123 AC: 18 AN: 1461236 Hom.: 0 Cov.: 31 AF XY: 0.0000124 AC XY: 9 AN XY: 726996

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000562

Gnomad4 NFE exome AF: 0.0000117

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Benign

Submissions summary: Uncertain:7 Benign:5

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1 Uncertain:3 Benign:1

Jan 18, 2017

Counsyl

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 18, 2019

Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)

Significance: Benign

Review Status: reviewed by expert panel

Collection Method: curation

IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 1 based on posterior probability = 0.000759 -

Jan 11, 2024

All of Us Research Program, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces arginine with tryptophan at codon 170 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).Functional studies have reported that this variant does not impact BRCA1 in on growth and homology-directed DNA repair assays in mouse Brca1-null embryonic stem cells (PMID: 23867111, 32546644). This variant has been reported in an individual affected with breast cancer (PMID: 25186627) and in a breast cancer case-control meta-analysis in 2/60466 cases and 0/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA1_001411). This variant also has been reported in a breast cancer case-control study and a pancreatic cancer case-control study in which this variant is absent in cases and found only in one unaffected individual in the control cohort (PMID: 30287823, 32980694). A multifactorial analysis has reported likelihood ratios for pathogenicity based on tumor pathology, co-occurrence with a pathogenic variant and family history of 0.544, 1.0673, 0.0641, respectively (PMID: 31131967). This variant has been identified in 3/251458 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. -

Nov 25, 2004

Breast Cancer Information Core (BIC) (BRCA1)

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not specified Benign:3

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 02, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 08, 2024

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

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: BRCA1 c.508C>T (p.Arg170Trp) results in a non-conservative amino acid change in the encoded protein sequence. Four 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 251458 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.508C>T has been reported in the literature in individuals affected with Breast Cancer (example, Tung_2014) as well as an unaffected Japanese male control (Momozawa_2018). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. At least one publication reports experimental evidence evaluating an impact on protein function (Bouwman_2013, Bouwman_2020). These results showed no damaging effect of this variant based on cisplatin response. The following publications have been ascertained in the context of this evaluation (PMID: 23867111, 25186627, 30287823, 31112341, 32546644). ClinVar contains an entry for this variant (Variation ID: 55393). Based on the evidence outlined above, the variant was classified as likely benign. -

not provided Uncertain:2

Dec 21, 2023

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate no damaging effect to cell growth, ubiquitination, or sensitivity to cisplatin (PMID: 23867111, 25823446, 32546644); 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); Also known as 627C>T; This variant is associated with the following publications: (PMID: 10923033, 23983145, 23867111, 30287823, 33087888, Rodriguez2013[CaseReport], 25823446, 31112341, 33471991, 36243179, 32546644, 20215511, 25186627, 31131967) -

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Uncertain:2

Jun 01, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R170W variant (also known as c.508C>T), located in coding exon 6 of the BRCA1 gene, results from a C to T substitution at nucleotide position 508. The arginine at codon 170 is replaced by tryptophan, an amino acid with dissimilar properties. Functional analysis of this alteration using cDNA-based functional complementation assays in mouse embryonic stem cells demonstrated that this alteration resulted in similar proliferation rates as wildtype, and was not deleterious based on cisplatin sensitivity assays (Bouwman P et al. Cancer Discov 2013 Oct; 3(10):1142-55). This alteration was not observed in unselected male breast cancer patients but was observed with an allele frequency of 0.0001 in 12490 male controls of Japanese ancestry (Momozawa Y et al. Nat Commun, 2018 10;9:4083). This variant was also reported in 2/60,466 breast cancer cases and in 0/53,461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). This amino acid position is poorly 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. -

Oct 05, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces arginine with tryptophan at codon 170 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).Functional studies have reported that this variant does not impact BRCA1 in on growth and homology-directed DNA repair assays in mouse Brca1-null embryonic stem cells (PMID: 23867111, 32546644). This variant has been reported in an individual affected with breast cancer (PMID: 25186627) and in a breast cancer case-control meta-analysis in 2/60466 cases and 0/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA1_001411). This variant also has been reported in a breast cancer case-control study and a pancreatic cancer case-control study in which this variant is absent in cases and found only in one unaffected individual in the control cohort (PMID: 30287823, 32980694). A multifactorial analysis has reported likelihood ratios for pathogenicity based on tumor pathology, co-occurrence with a pathogenic variant and family history of 0.544, 1.0673, 0.0641, respectively (PMID: 31131967). This variant has been identified in 3/251458 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. -

Hereditary breast ovarian cancer syndrome Benign:1

Aug 04, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	0.020
CADD	Benign	19
DANN	Benign	0.96
DEOGEN2	Benign	0.11	.;T;.;.;.;.;.;T;.;T;.;T;T;.;T;T
Eigen	Benign	-0.95
Eigen_PC	Benign	-0.83
FATHMM_MKL	Benign	0.054	N
LIST_S2	Uncertain	0.89	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Uncertain	0.087	D
MetaRNN	Benign	0.081	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.074	T
MutationAssessor	Benign	-0.69	N;N;N;N;.;N;.;.;.;.;.;.;.;.;.;.
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-2.1	N;N;N;D;N;D;N;N;N;D;N;.;N;N;N;D
REVEL	Uncertain	0.48
Sift	Uncertain	0.0030	D;D;T;D;D;D;D;D;D;D;T;.;D;T;D;D
Sift4G	Uncertain	0.015	D;T;T;T;T;T;.;.;D;.;T;.;D;.;D;.
Polyphen		0.0, 0.0010	.;B;.;.;.;B;.;B;.;.;B;.;.;.;.;.
Vest4		0.27
MutPred		0.41		Loss of disorder (P = 0.0062);Loss of disorder (P = 0.0062);Loss of disorder (P = 0.0062);Loss of disorder (P = 0.0062);.;Loss of disorder (P = 0.0062);.;.;.;.;Loss of disorder (P = 0.0062);Loss of disorder (P = 0.0062);Loss of disorder (P = 0.0062);.;Loss of disorder (P = 0.0062);.;
MVP		0.59
MPC		0.084
ClinPred		0.16	T
GERP RS		1.8
Varity_R		0.036
gMVP		0.25

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs80357325; hg19: chr17-41251831;