Reference Detail

Ref Type

Journal Article

PMID

(33933153)

Authors

Zheng Y, Li B, Pan D, Cao J, Zhang J, Wang X, Li X, Hou W, Bao D, Ren L, Yang J, Wang S, Qiu Y, Zhou F, Liu Z, Zhu S, Zhang L, Qing T, Wang Y, Yu Y, Wu J, Hu X, Shi L

Title

Functional consequences of a rare missense BARD1 c.403G>A germline mutation identified in a triple-negative breast cancer patient.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Breast cancer research : BCR	23	1	2021 05 01	53	Breast Cancer Res

URL

Abstract Text

We identified a rare missense germline mutation in BARD1 (c.403G>A or p.Asp135Asn) as pathogenic using integrated genomics and transcriptomics profiling of germline and tumor samples from an early-onset triple-negative breast cancer patient who later was administrated with a PARP inhibitor for 2 months. We demonstrated in cell and mouse models that, compared to the wild-type, (1) c.403G>A mutant cell lines were more sensitive to irradiation, a DNA damage agent, and a PARP inhibitor; (2) c.403G>A mutation inhibited interaction between BARD1 and RAD51 (but not BRCA1); and (3) c.403G>A mutant mice were hypersensitive to ionizing radiation. Our study shed lights on the clinical interpretation of rare germline mutations of BARD1.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

Gene	Variant	Impact	Protein Effect	Variant Description
BARD1	A638T	missense	unknown	BARD1 A638T lies within BRCT domain 1 of the Bard1 protein (UniProt.org). A638T has been identified in sequencing studies (PMID: 33933153), but has not been biochemically characterized and therefore, its effect on Bard1 protein function is unknown (PubMed, Nov 2023).
BARD1	D135N	missense	loss of function	BARD1 D135N lies within the RAD51-interacting domain of the Bard1 protein (PMID: 28976962). D135N results in Brca1 interaction similar to wild-type Bard1 but decreased Rad51 interaction and increased sensitivity to DNA damage upon irradiation in culture and in mouse models (PMID: 33933153).
BARD1	P24_A25insGTSLVPP	insertion	unknown	BARD1 P24_A25insGTSLVPP results in the insertion of seven amino acids in the Bard1 protein between amino acids 24 and 25 (UniProt.org). P24_A25insGTSLVPP (referred to as A23delinsAPGTSLVP) has been identified in sequencing studies (PMID: 33933153), but has not been biochemically characterized and therefore, its effect on Bard1 protein function is unknown (PubMed, Nov 2023).
BARD1	R529Q	missense	unknown	BARD1 R529Q lies within ANK repeat 4 of the Bard1 protein (UniProt.org). R529Q has been identified in sequencing studies (PMID: 33933153), but has not been biochemically characterized and therefore, its effect on Bard1 protein function is unknown (PubMed, Nov 2023).
BARD1	T716N	missense	unknown	BARD1 T716N lies within BRCT domain 2 of the Bard1 protein (UniProt.org). T716N has been identified in sequencing studies (PMID: 33933153), but has not been biochemically characterized and therefore, its effect on Bard1 protein function is unknown (PubMed, Nov 2023).

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
BARD1 D135N	breast cancer	predicted - sensitive	Fluzoparib	Preclinical - Cell culture	Actionable	In a preclinical study, Fluzoparib (SHR3162) treatment inhibited proliferation of a BARD1-deficient breast cancer cell line expressing BARD1 D135N in culture (PMID: 33933153).	33933153